Contributed equally to this work with:
Huaichuan Duan,
Quanshan Shi
Roles
Conceptualization,
Data curation,
Writing – original draft
Affiliation
Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
Contributed equally to this work with:
Huaichuan Duan,
Quanshan Shi
Roles
Conceptualization,
Software
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, China
Affiliation
Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
This paper was transferred from another journal. As a result, its full editorial history
(including decision letters, peer reviews and author responses) may not be present.
PONE-D-24-03917Development of mechanism‐based inhibitor against Monkeypox virus: A WEB to predict
the binding patternsPLOS ONE
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Reviewer #1: Partly
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**********
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Reviewer #1: In this study the authors claim to have developed a monkeypox core protein
library and a library of inhibitors targeting these core proteins. The authors have
in addition built a docking server that predicts the binding modes between the protein
and the substrate to understand the molecular dialogues between these entities. Currently
there are hardly such servers dedicated for monkeypox virus. Therefore, such an endeavour
is greatly welcome. Although the paper appears to be sound overall, I have some key
recommendations that that I think can be incorporated before the paper can be accepted
for publication.
1. In the methodology section method 2.1.Open reading frame (ORF), the ORF needs to
be defined more concretely. I advise the authors to have a look at the results section
(3.1 The meaning of the open reading frame (ORF) and core proteins in this study)
of the paper titled “Identification of core therapeutic targets for Monkeypox virus
andrepurposing potential of drugs against them: An in silico approach”for better clarity.
2. Similarly, the term core protein creates a lot of confusion. From the view of a
genomics researcher core protein is more closely associated with proteins that are
highly conserved across all the genomes. However, from the point of view of a classical
virologist core protein usually means the structural protein embedded on the outer
membranes that give a virus its definitive shape. Therefore, the authors should clearly
mention this in the manuscript as readers will comprise of people from multiple disciplines.
Again, I advise the authors to have a look at the results section (3.1 The meaning
of the open reading frame (ORF) and core proteins in this study) of the paper titled
“Identification of core therapeutic targets for Monkeypox virus and repurposing potential
of drugs against them: An in silico approach”for better clarity.
3. Shared host homology is one of the biggest reasons for the failure of a drug from
reaching the bed from the bench. This often creates adverse reactions by to off-targeting
the host proteins instead. As a consequence, drugs often fail during clinical trials.
Therefore, the authors must verify that the 12 key proteins do not share homology
with human proteins beyond an allowable threshold (usually e-value of 0.0001 against
the entire set of human proteome dataset (taxid: 9606) is considered a good threshold).
The authors must provide this information in the manuscript.
4. Why only 12 proteins were selected as targets? Are all the 12 key proteins druggable?
The authors need to verify this information as not all proteins present highly druggable
surfaces for docking. The validity of the structures used for docking should be more
adequately demonstrated.
5. Are any of the proteins intrinsically disordered? This is a very key question that
needs answering. They are a fascinating class of proteins that lack a fixed or well-defined
three-dimensional structure in their free state. Therefore, docking against such proteins
are more challenging than what meets the eye. Therefore, physiochemical properties
like isoelectric point (pI), molecular weight, aliphatic index, instability index,
extinction co-efficient and residues accessibility of the 12 key proteins must be
examined and provided in the manuscript. This data will aid experimental biologists
to choose suitable proteins for experimental validation.
Overall, the proteins that are highly conserved, non-host homologous, highly druggable
are usually considered very high value therapeutic targets. The proteins that ensure
these features are likely to have a higher rate of success. Hence, I feel these key
points need to be investigated by the authors before being considered for final consideration.
The above recommended paper should aid the authors in this endeavour.
6. The efficiency of the docking server is not demonstrated with appropriate controls.
Since, none of the results are experimentally validated, it is necessary to demonstrate
the efficiency by comparison with other docking models.
Reviewer #2: The paper titled “Development of mechanism‐based inhibitor against Monkeypox
virus: A WEB to predict the binding patterns” is like a review on the said “Monkeypox
virus Docking Server”. The server might serve as a good resource for people working
on the virus, which is indeed comprehensive and well-thought-out. It can perform modeling,
docking, and annotation. Still, it lacks a firm basis, and improvement is needed.
The issues pointed out below are critical and need to be properly addressed:
1. The key to publishing a paper on a developed tool is to put forth a detailed analysis
concerning the accuracy of the results yielded by it through statistical inferences.
The authors have presented an example but it's not enough to validate the potentiality
of the server.
2. It is clear that the server provides functional annotations for specific genes
or proteins of interest, but are there tools or functionalities available for analyzing
gene function, protein structure, or pathway enrichment? How does the server facilitate
the comparative analysis of genes, proteins, or genomes across different ortho-poxviruses?
It would be interesting if there were such a provision that the server could carry
out.
3. Have the authors conducted site-specific docking or blind docking methodologies
in this investigation? Please provide a clear explanation. It's not clear how, in
case of no active site details, the tool can locate an active site for a newly modeled
protein by reverse docking. The authors need to elaborate on that.
4. Given that a significant portion of the protein crystal structures remains unresolved,
the authors generated homology models to address this limitation. How did the authors
predict the orthosteric sites of the protein targets? Was a validation conducted against
known inhibitors to assess the accuracy of the predicted orthosteric sites?
5. If the authors have not undertaken validation utilizing established inhibitors
against the protein targets, I recommend conducting a benchmark study for comprehensive
evaluation.
6. What rationale led the authors to choose AutoDock Vina? Kindly elucidate the justification
for this selection. Additionally, is it feasible to conduct reverse screening of peptide-like
inhibitors using the web server?
7. The authors must mention how their server is unique/better than similar tools developed
in the past, such as the 'COVID-19 Docking Server'.
8. In the literature study in the introduction, the authors should also cite one recent
exciting work published in ACS JPCL, where the authors modeled the P37 protein of
MPXV using the AF tool and performed computer-aided drug discovery. The paper suits
the context of the webserver as well the manuscript. https://doi.org/10.1021/acs.jpclett.3c00087
9. Additionally, the authors are advised to improve the website to make it more user-friendly:
a. The user interface must be made to look interesting and organized. Various visualization
tools are now available to present 3D protein structures and interactions. The authors
should work on it.
b. The authors should think of a simple one/two-worded name for the server, implying
that it is a docking server meant only for MPXV proteins and also serves as a comprehensive
database.
c. The manuscript title can also be improved. It does not resonate with the work done
or the core feature of the server.
Evaluating the quality of the work as well as the existing drawbacks, the paper can
be recommended for publication in PLOS ONE only after the above-mentioned revisions.
Apparently, this is the first MPXV webserver. The authors should do major work to
improve it and publish it.
**********
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Reviewer #1: Yes: Bharat Bhusan Subudhi
Reviewer #2: No
**********
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Thank you very much for your email of Major decision, regarding our manuscript Development
of mechanism‐based inhibitor against Monkeypox virus: A WEB to predict the binding
patterns (Manuscript Number: PONE-D-24-03917R1).
We would like to thank wholeheartedly the referees for their valuable and helpful
comments about our manuscript. Thanks to the reviewers for their recognition of the
research objectives, rationale and methods of the article, as well as confirming the
experimental data of the article. Suggestions on the figures and structure of the
article will also be listened to and improved upon. Our replies to reviewers’ comments
are enclosed below and in the revised version of the manuscript, we marked two parts
in red: the suggestions given by the reviewers and the contents modified by the second
reading of the article. We hope that our revised manuscript is now suitable for publication
in PLOS ONE.
Thank you to the editors for their advice on article acceptance. We have reconfirmed
PLOS-ONE's requirements for articles as well as shared code to ensure that the submitted
manuscripts are in order. Second, the funder had no role in the study design, data
collection and analysis, publication decision, or preparation of the manuscript. Additionally,
the editor mentioned a data sharing program, and we accept the editor's suggestion
that we can accept sharing of data prior to article acceptance. The editor also raised
the issue of copyright, and we were acutely aware of the importance of copyright,
so we corrected the article and removed Figure s.17 Finally, for the supporting material
we made a separate file and made sure that each information file had a legend in the
manuscript following the list of references.
Reply to Reviewer 1
In this study the authors claim to have developed a monkeypox core protein library
and a library of inhibitors targeting these core proteins. The authors have in addition
built a docking server that predicts the binding modes between the protein and the
substrate to understand the molecular dialogues between these entities. Currently
there are hardly such servers dedicated for monkeypox virus. Therefore, such an endeavor
is greatly welcome. Although the paper appears to be sound overall, I have some key
recommendations that that I think can be incorporated before the paper can be accepted
for publication.
Specific comment 1
In the methodology section method 2.1. Open reading frame (ORF), the ORF needs to
be defined more concretely. I advise the authors to have a look at the results section
(3.1 The meaning of the open reading frame (ORF) and core proteins in this study)
of the paper titled “ Identification of core therapeutic targets for Monkeypox virus
and repurposing potential of drugs against them: An in silico approach ”for better
clarity.
Response 1
I appreciate the editor's comments and I have taken the time to check out the full
article. The Open Reading Frame (ORF) serves as the beginning of the article and has
an important role in the subsequent work. In the Methods section we considered the
length of the article, so we simply explained the ORF. In response to the editor's
suggestion, we have explained this section in more detail, and the specific corrections
are as follows:
ORF is a fundamental concept in molecular bioinformatics, it is the normal nucleotide
sequence of a structural gene, the reading frame from the start codon to the stop
codon can encode a complete polypeptide chain, between which there is no stop codon
that interrupts the translation. The term open refers to the "open" region of an intact
gene used for protein translation, and reading frame refers to one of the six possibilities
for translation of a double-stranded gene sequence into amino acids. In molecular
biology, the detection of ORFs is an important step in the discovery of specific protein-coding
genes in the genome sequence, and can serve as an indicator of a potential protein-coding
gene. In our work, the acquisition of ORF mainly includes literature reading and database
research.
In addition to the suggestions for ORFs, the editors also made a suggestion to change
the title of the article to "Identification of core therapeutic targets for Monkeypox
virus and repurposing potential of drugs against They: An in-silico approach", which
is more in accordance with the content of the article. In our very first title, we
targeted the server, ignoring the fact that the article studies more on monkeypox
virus and core proteins. Seeing the editor's suggestion, we appreciate being able
to identify this issue and also think that changing the title would benefit the article
more.
Specific comment 2
Similarly, the term core protein creates a lot of confusion. From the view of a genomics
researcher core protein is more closely associated with proteins that are highly conserved
across all the genomes. However, from the point of view of a classical virologist
core protein usually means the structural protein embedded on the outer membranes
that give a virus its definitive shape. Therefore, the authors should clearly mention
this in the manuscript as readers will comprise of people from multiple disciplines.
Again, I advise the authors to have a look at the results section (3.1 The meaning
of the open reading frame (ORF) and core proteins in this study) of the paper titled
“Identification of core therapeutic targets for Monkeypox virus and repurposing potential
of drugs against them: An in-silico approach” for better clarity.
Response 2
We thank the reviewers for this suggestion, and we do recognize the reviewers' suggestion
that the core proteins were improperly worded. In our work, core proteins are used
to denote potential proteins with the potential to inhibit monkeypox virus, and do
not refer to structural proteins or highly conserved proteins as mentioned by the
reviewer. In order to avoid misunderstanding, we have corrected all references to
core proteins in the article and replaced the original core proteins with potential
targets. The following are some of the corrections:
A new round of monkeypox virus has emerged in the United Kingdom since July 2022 and
rapidly swept the world. Currently, despite numerous research groups are studying
this virus and seeking effective treatments, the information on the open reading frame,
inhibitors, and potential targets of monkeypox has not been updated in time, and the
comprehension of monkeypox target ligand interactions remains a key challenge. Here,
we first summarized and improved the open reading frame information of monkeypox,
constructed the monkeypox inhibitor library and potential targets library by database
research as well as literature search, combined with advanced protein modeling technologies
(Sequence-based and AI algorithms-based homology modeling). In addition, we build
monkeypox virus Docking Server, a web server to predict the binding mode between targets
and substrate. The open reading frame information, monkeypox inhibitor library, and
monkeypox potential targets library are used as the initial files for server docking,
providing free interactive tools for predicting ligand interactions of monkeypox targets,
potential drug screening, and potential targets search. In addition, the update of
the three databases can also effectively promote the study of monkeypox drug inhibition
mechanism and provide theoretical guidance for the development of drugs for monkeypox.
In this issue, the reviewer again proposed a change in the title of the article. In
the previous comment, we clearly stated that we recognized the reviewer's title and
explained the reason for the title in the first place. Again, we thank the reviewers
for their attention to this issue.
Specific comment 3
Shared host homology is one of the biggest reasons for the failure of a drug from
reaching the bed from the bench. This often creates adverse reactions by to off-targeting
the host proteins instead. As a consequence, drugs often fail during clinical trials.
Therefore, the authors must verify that the 12 key proteins do not share homology
with human proteins beyond an allowable threshold (usually e-value of 0.0001 against
the entire set of human proteome dataset (taxid: 9606) is considered a good threshold).
The authors must provide this information in the manuscript.
Response 3
This question raised by the reviewer is very interesting and we have addressed it
with a detailed explanation. Shared host homology as an important issue that must
be considered for subsequent drug development, if the homology is too high it will
lead to poor drug selectivity, and attacking the viral cells while also harming the
host cells to a certain extent. In our article, this issue was neglected, so in the
revised manuscript, for both host and viral cells we added this part. This includes
calculation of physicochemical information of 12 proteins, sequence similarity with
human-derived proteins, VAC, VAR and CPV, detailing the host homology issue.
The three-dimensional structure of proteins is an important basis for understanding
their biological functions and for structure-based drug design [104]. With the rapid
development of structural biology, the speed of measuring protein 3D structures using
methods such as NMR, X-Ray or cryoelectronic microscopy (Cryo-EM) crystallography
has been greatly improved [39, 105]. However, the 3D structures of some proteins are
still difficult to determine due to many reasons, such as excessive molecular weight
or difficulty in crystallization. Before modeling the protein structures, we first
performed a series of physicochemical property analyses on 12 potential target sequences,
including Weight, PI, Extinction, Instability, Aliphatic and Hydrophathicity, and
compared the sequences of monkeypox with those of human origin and other orthopox
viruses (table s1). It was found that the structural domains of the proteins were
stabilized to a certain extent and could be used for subsequent studies; The sequence
similarity of all proteins except D6L was less than 60% to human, which avoided the
side effects of the drug caused by host homology. D6L, as an interleukin-18 binding
protein homologous to the host, functionally affirmed its high sequence similarity
to human proteins, a characteristic that also increased the difficulty of developing
drugs against it; finally, the sequence similarity between monkeypox virus and orthopoxvirus
was higher than 78%, proving the existence of commonality between them, and providing
an opportunity to seek possible orthopoxvirus-based drugs for the subsequent studies.
This lays a theoretical foundation for the search of possible monkeypox virus drugs
based on orthopox viruses.
For the key proteins of monkeypox, we found that eight (A49R, C3L, H1L, E4R, C7L,
A41L, D6L and E13L) could be obtained from orthopox viruses (VAR, VAC and MPV) modeled
with high sequence similarity. As for the key proteins (A22R, I7L, C19L and A50R),
which are not present in any of the orthopoxvirus genera, we chose AlphaFold2, which
is only one atomic width away from the true structure for most of the predicted protein
structures, to predict them. Notably that based on the multifaceted superiority, AlphaFold2
reaches the level of prediction observed by sophisticated instruments such as cryoelectron
microscopy, which can effectively guarantee the accuracy of the predicted structures
(Fig.2) [106]. Hence, we constructed a database of orthopoxvirus proteins with a capacity
of 45.
Table s1 Physicochemical properties of 12 potential target protein sequences and sequence
similarity to human and orthopoxvirus
Why only 12 proteins were selected as targets? Are all the 12 key proteins druggable?
The authors need to verify this information as not all proteins present highly druggable
surfaces for docking. The validity of the structures used for docking should be more
adequately demonstrated.
Response 4
We are grateful to the reviewers for raising the issue of proteins druggable, and
we will provide answers to each of the questions raised. Firstly, about the 12 target
proteins selected: in the preliminary background research, this work extensively read
all the articles (more than 1,000) on orthopox viruses since the first outbreak to
seek for key targets that might inhibit orthopox viruses. During infection, a large
number of proteins are involved in the process of virus invasion, replication, envelopment
and release, and the virus can be effectively inhibited by inhibiting these key proteins.
Based on literature research, 12 key proteins with important roles for the virus were
finally searched and identified by summarizing the studies of various infection processes.
The whole work does not involve screening proteins, but rather investigating all the
targets that have been clearly shown to be potential in studies. The second problem
is for the proteins druggable: the treatment of monkeypox is still in the exploratory
stage, and there is no specific drug that can effectively deal with it. The 12 target
proteins are all shown to be potentially druggable, and each protein is clearly described
in section 3.2 of the article, explaining why it is a potential target for monkeypox
treatment. In addition, all 12 proteins have clear docking sites, which were identified
by previous researchers through various chemical experiments, not just theoretical
descriptions. So, in response to the reviewer's question about the validity of the
docking structure I think there is no problem.
Specific comment 5
Are any of the proteins intrinsically disordered? This is a very key question that
needs answering. They are a fascinating class of proteins that lack a fixed or well-defined
three-dimensional structure in their free state. Therefore, docking against such proteins
are more challenging than what meets the eye. Therefore, physiochemical properties
like isoelectric point (pI), molecular weight, aliphatic index, instability index,
extinction co-efficient and residues accessibility of the 12 key proteins must be
examined and provided in the manuscript. This data will aid experimental biologists
to choose suitable proteins for experimental validation.
Overall, the proteins that are highly conserved, non-host homologous, highly druggable
are usually considered very high value therapeutic targets. The proteins that ensure
these features are likely to have a higher rate of success. Hence, I feel these key
points need to be investigated by the authors before being considered for final consideration.
The above recommended paper should aid the authors in this endeavor.
Response 5
We recognize in depth the issues raised by the reviewers. Among the 12 proteins we
studied, there is no disordered protein structure. The three-dimensional structure
of proteins serves as an important basis for understanding their biological functions
and structure-based drug design. Using homologous mode-bonding technique, we obtained
monkeypox target protein structures based on eight (A49R, C3L, H1L, E4R, C7L, A41L,
D6L, and E13L) orthopoxviral (VAR, VAC, and CPV) proteins that were already available
as templates. As for the key proteins (A22R, I7L, C19L and A50R), which a
PONE-D-24-03917R1Identification of core therapeutic targets for Monkeypox virus and repurposing potential
of drugs against them: an in-silico approachPLOS ONE
Dear Dr. Hu,
Thank you for submitting your manuscript to PLOS ONE.
Please address this concern explaining the similarities and differences between the
two articles.
Please submit your revised manuscript by Jul 05 2024 11:59PM. If you will need more
time than this to complete your revisions, please reply to this message or contact
the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.
Please address this concern explaining the similarities and differences between the
two articles.
[Note: HTML markup is below. Please do not edit.]
[NOTE: If reviewer comments were submitted as an attachment file, they will be attached
to this email and accessible via the submission site. Please log into your account,
locate the manuscript record, and check for the action link "View Attachments". If
this link does not appear, there are no attachment files.]
While revising your submission, please upload your figure files to the Preflight Analysis
and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first
register as a user. Registration is free. Then, login and navigate to the UPLOAD tab,
where you will find detailed instructions on how to use the tool. If you encounter
any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
Thank you very much for your email of Major decision, regarding our manuscript: Identifying
the core therapeutic targets of monkeypox virus and the repurposing potential of orthopox
inhibitors: an in-silico approach (Manuscript Number: PONE-D-24-03917R1).
It's good to hear from you, and we're responding to the questions mentioned by Editor.
First of all, our article is duplicated with another article title. When the reviewer
gave his comments, he suggested us to change the title several times and gave us this
title. At that time, we thought the title was suitable for our article and applied
it, forgetting to check whether it was a duplicate of another article's title. We
will revise the title of the article appropriately. Secondly, the editor mentioned
that the article has similarity in content. Both articles were used as the core therapeutic
target of monkeypox protein, and it is necessary to understand the story behind monkeypox.
In addition, the focus of the two articles is different, our article mainly focuses
on the important targets and potential inhibitors of monkeypox to screen possible
drugs and speculate other targets, while the other article focuses on the connection
between specific targets and inhibitors. The originality of the article is a must
for every researcher, and we guarantee that there is no plagiarism or falsification
in the writing and experimental process of this article.
We look forward to receiving your revised manuscript.
PONE-D-24-03917R2Identifying the core therapeutic targets of monkeypox virus and the repurposing potential
of orthopox inhibitors: an in-silico approachPLOS ONE
Dear Dr. Hu,
Thank you for submitting your manuscript to PLOS ONE. After careful consideration,
we feel that it has merit but does not fully meet PLOS ONE’s publication criteria
as it currently stands. Therefore, we invite you to submit a revised version of the
manuscript that addresses the points raised during the review process.
Please submit your revised manuscript by Jul 08 2024 11:59PM. If you will need more
time than this to complete your revisions, please reply to this message or contact
the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.
Please include the following items when submitting your revised manuscript:
A rebuttal letter that responds to each point raised by the academic editor and reviewer(s).
You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version.
You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload
this as a separate file labeled 'Manuscript'.
If you would like to make changes to your financial disclosure, please include your
updated statement in your cover letter. Guidelines for resubmitting your figure files
are available below the reviewer comments at the end of this letter.
We look forward to receiving your revised manuscript.
Kind regards,
Mahmoud Kandeel
Academic Editor
PLOS ONE
Journal Requirements:
Please review your reference list to ensure that it is complete and correct. If you
have cited papers that have been retracted, please include the rationale for doing
so in the manuscript text, or remove these references and replace them with relevant
current references. Any changes to the reference list should be mentioned in the rebuttal
letter that accompanies your revised manuscript. If you need to cite a retracted article,
indicate the article’s retracted status in the References list and also include a
citation and full reference for the retraction notice.
Additional Editor Comments:
Please rewrite the title of the manuscript, to avoid overlapping and similarity with
the previously published article. The title must clearly express the content of your
manuscript.
[Note: HTML markup is below. Please do not edit.]
[NOTE: If reviewer comments were submitted as an attachment file, they will be attached
to this email and accessible via the submission site. Please log into your account,
locate the manuscript record, and check for the action link "View Attachments". If
this link does not appear, there are no attachment files.]
While revising your submission, please upload your figure files to the Preflight Analysis
and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first
register as a user. Registration is free. Then, login and navigate to the UPLOAD tab,
where you will find detailed instructions on how to use the tool. If you encounter
any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
Thank you very much for your email of Major decision, regarding our manuscript Development
of mechanism‐based inhibitor against Monkeypox virus: A WEB to predict the binding
patterns (Manuscript Number: PONE-D-24-03917R1).
We would like to thank wholeheartedly the referees for their valuable and helpful
comments about our manuscript. Thanks to the reviewers for their recognition of the
research objectives, rationale and methods of the article, as well as confirming the
experimental data of the article. Suggestions on the figures and structure of the
article will also be listened to and improved upon. Our replies to reviewers’ comments
are enclosed below and in the revised version of the manuscript, we marked two parts
in red: the suggestions given by the reviewers and the contents modified by the second
reading of the article. We hope that our revised manuscript is now suitable for publication
in PLOS ONE.
Thank you to the editors for their advice on article acceptance. We have reconfirmed
PLOS-ONE's requirements for articles as well as shared code to ensure that the submitted
manuscripts are in order. Second, the funder had no role in the study design, data
collection and analysis, publication decision, or preparation of the manuscript. Additionally,
the editor mentioned a data sharing program, and we accept the editor's suggestion
that we can accept sharing of data prior to article acceptance. The editor also raised
the issue of copyright, and we were acutely aware of the importance of copyright,
so we corrected the article and removed Figure s.17 Finally, for the supporting material
we made a separate file and made sure that each information file had a legend in the
manuscript following the list of references.
Reply to Reviewer 1
In this study the authors claim to have developed a monkeypox core protein library
and a library of inhibitors targeting these core proteins. The authors have in addition
built a docking server that predicts the binding modes between the protein and the
substrate to understand the molecular dialogues between these entities. Currently
there are hardly such servers dedicated for monkeypox virus. Therefore, such an endeavor
is greatly welcome. Although the paper appears to be sound overall, I have some key
recommendations that that I think can be incorporated before the paper can be accepted
for publication.
Specific comment 1
In the methodology section method 2.1. Open reading frame (ORF), the ORF needs to
be defined more concretely. I advise the authors to have a look at the results section
(3.1 The meaning of the open reading frame (ORF) and core proteins in this study)
of the paper titled “ Identification of core therapeutic targets for Monkeypox virus
and repurposing potential of drugs against them: An in silico approach ”for better
clarity.
Response 1
I appreciate the editor's comments and I have taken the time to check out the full
article. The Open Reading Frame (ORF) serves as the beginning of the article and has
an important role in the subsequent work. In the Methods section we considered the
length of the article, so we simply explained the ORF. In response to the editor's
suggestion, we have explained this section in more detail, and the specific corrections
are as follows:
ORF is a fundamental concept in molecular bioinformatics, it is the normal nucleotide
sequence of a structural gene, the reading frame from the start codon to the stop
codon can encode a complete polypeptide chain, between which there is no stop codon
that interrupts the translation. The term open refers to the "open" region of an intact
gene used for protein translation, and reading frame refers to one of the six possibilities
for translation of a double-stranded gene sequence into amino acids. In molecular
biology, the detection of ORFs is an important step in the discovery of specific protein-coding
genes in the genome sequence, and can serve as an indicator of a potential protein-coding
gene. In our work, the acquisition of ORF mainly includes literature reading and database
research.
In addition to the suggestions for ORFs, the editors also made a suggestion to change
the title of the article to "Identification of core therapeutic targets for Monkeypox
virus and repurposing potential of drugs against They: An in-silico approach", which
is more in accordance with the content of the article. In our very first title, we
targeted the server, ignoring the fact that the article studies more on monkeypox
virus and core proteins. Seeing the editor's suggestion, we appreciate being able
to identify this issue and also think that changing the title would benefit the article
more.
Specific comment 2
Similarly, the term core protein creates a lot of confusion. From the view of a genomics
researcher core protein is more closely associated with proteins that are highly conserved
across all the genomes. However, from the point of view of a classical virologist
core protein usually means the structural protein embedded on the outer membranes
that give a virus its definitive shape. Therefore, the authors should clearly mention
this in the manuscript as readers will comprise of people from multiple disciplines.
Again, I advise the authors to have a look at the results section (3.1 The meaning
of the open reading frame (ORF) and core proteins in this study) of the paper titled
“Identification of core therapeutic targets for Monkeypox virus and repurposing potential
of drugs against them: An in-silico approach” for better clarity.
Response 2
We thank the reviewers for this suggestion, and we do recognize the reviewers' suggestion
that the core proteins were improperly worded. In our work, core proteins are used
to denote potential proteins with the potential to inhibit monkeypox virus, and do
not refer to structural proteins or highly conserved proteins as mentioned by the
reviewer. In order to avoid misunderstanding, we have corrected all references to
core proteins in the article and replaced the original core proteins with potential
targets. The following are some of the corrections:
A new round of monkeypox virus has emerged in the United Kingdom since July 2022 and
rapidly swept the world. Currently, despite numerous research groups are studying
this virus and seeking effective treatments, the information on the open reading frame,
inhibitors, and potential targets of monkeypox has not been updated in time, and the
comprehension of monkeypox target ligand interactions remains a key challenge. Here,
we first summarized and improved the open reading frame information of monkeypox,
constructed the monkeypox inhibitor library and potential targets library by database
research as well as literature search, combined with advanced protein modeling technologies
(Sequence-based and AI algorithms-based homology modeling). In addition, we build
monkeypox virus Docking Server, a web server to predict the binding mode between targets
and substrate. The open reading frame information, monkeypox inhibitor library, and
monkeypox potential targets library are used as the initial files for server docking,
providing free interactive tools for predicting ligand interactions of monkeypox targets,
potential drug screening, and potential targets search. In addition, the update of
the three databases can also effectively promote the study of monkeypox drug inhibition
mechanism and provide theoretical guidance for the development of drugs for monkeypox.
In this issue, the reviewer again proposed a change in the title of the article. In
the previous comment, we clearly stated that we recognized the reviewer's title and
explained the reason for the title in the first place. Again, we thank the reviewers
for their attention to this issue.
Specific comment 3
Shared host homology is one of the biggest reasons for the failure of a drug from
reaching the bed from the bench. This often creates adverse reactions by to off-targeting
the host proteins instead. As a consequence, drugs often fail during clinical trials.
Therefore, the authors must verify that the 12 key proteins do not share homology
with human proteins beyond an allowable threshold (usually e-value of 0.0001 against
the entire set of human proteome dataset (taxid: 9606) is considered a good threshold).
The authors must provide this information in the manuscript.
Response 3
This question raised by the reviewer is very interesting and we have addressed it
with a detailed explanation. Shared host homology as an important issue that must
be considered for subsequent drug development, if the homology is too high it will
lead to poor drug selectivity, and attacking the viral cells while also harming the
host cells to a certain extent. In our article, this issue was neglected, so in the
revised manuscript, for both host and viral cells we added this part. This includes
calculation of physicochemical information of 12 proteins, sequence similarity with
human-derived proteins, VAC, VAR and CPV, detailing the host homology issue.
The three-dimensional structure of proteins is an important basis for understanding
their biological functions and for structure-based drug design [104]. With the rapid
development of structural biology, the speed of measuring protein 3D structures using
methods such as NMR, X-Ray or cryoelectronic microscopy (Cryo-EM) crystallography
has been greatly improved [39, 105]. However, the 3D structures of some proteins are
still difficult to determine due to many reasons, such as excessive molecular weight
or difficulty in crystallization. Before modeling the protein structures, we first
performed a series of physicochemical property analyses on 12 potential target sequences,
including Weight, PI, Extinction, Instability, Aliphatic and Hydrophathicity, and
compared the sequences of monkeypox with those of human origin and other orthopox
viruses (table s1). It was found that the structural domains of the proteins were
stabilized to a certain extent and could be used for subsequent studies; The sequence
similarity of all proteins except D6L was less than 60% to human, which avoided the
side effects of the drug caused by host homology. D6L, as an interleukin-18 binding
protein homologous to the host, functionally affirmed its high sequence similarity
to human proteins, a characteristic that also increased the difficulty of developing
drugs against it; finally, the sequence similarity between monkeypox virus and orthopoxvirus
was higher than 78%, proving the existence of commonality between them, and providing
an opportunity to seek possible orthopoxvirus-based drugs for the subsequent studies.
This lays a theoretical foundation for the search of possible monkeypox virus drugs
based on orthopox viruses.
For the key proteins of monkeypox, we found that eight (A49R, C3L, H1L, E4R, C7L,
A41L, D6L and E13L) could be obtained from orthopox viruses (VAR, VAC and MPV) modeled
with high sequence similarity. As for the key proteins (A22R, I7L, C19L and A50R),
which are not present in any of the orthopoxvirus genera, we chose AlphaFold2, which
is only one atomic width away from the true structure for most of the predicted protein
structures, to predict them. Notably that based on the multifaceted superiority, AlphaFold2
reaches the level of prediction observed by sophisticated instruments such as cryoelectron
microscopy, which can effectively guarantee the accuracy of the predicted structures
(Fig.2) [106]. Hence, we constructed a database of orthopoxvirus proteins with a capacity
of 45.
Table s1 Physicochemical properties of 12 potential target protein sequences and sequence
similarity to human and orthopoxvirus
Why only 12 proteins were selected as targets? Are all the 12 key proteins druggable?
The authors need to verify this information as not all proteins present highly druggable
surfaces for docking. The validity of the structures used for docking should be more
adequately demonstrated.
Response 4
We are grateful to the reviewers for raising the issue of proteins druggable, and
we will provide answers to each of the questions raised. Firstly, about the 12 target
proteins selected: in the preliminary background research, this work extensively read
all the articles (more than 1,000) on orthopox viruses since the first outbreak to
seek for key targets that might inhibit orthopox viruses. During infection, a large
number of proteins are involved in the process of virus invasion, replication, envelopment
and release, and the virus can be effectively inhibited by inhibiting these key proteins.
Based on literature research, 12 key proteins with important roles for the virus were
finally searched and identified by summarizing the studies of various infection processes.
The whole work does not involve screening proteins, but rather investigating all the
targets that have been clearly shown to be potential in studies. The second problem
is for the proteins druggable: the treatment of monkeypox is still in the exploratory
stage, and there is no specific drug that can effectively deal with it. The 12 target
proteins are all shown to be potentially druggable, and each protein is clearly described
in section 3.2 of the article, explaining why it is a potential target for monkeypox
treatment. In addition, all 12 proteins have clear docking sites, which were identified
by previous researchers through various chemical experiments, not just theoretical
descriptions. So, in response to the reviewer's question about the validity of the
docking structure I think there is no problem.
Specific comment 5
Are any of the proteins intrinsically disordered? This is a very key question that
needs answering. They are a fascinating class of proteins that lack a fixed or well-defined
three-dimensional structure in their free state. Therefore, docking against such proteins
are more challenging than what meets the eye. Therefore, physiochemical properties
like isoelectric point (pI), molecular weight, aliphatic index, instability index,
extinction co-efficient and residues accessibility of the 12 key proteins must be
examined and provided in the manuscript. This data will aid experimental biologists
to choose suitable proteins for experimental validation.
Overall, the proteins that are highly conserved, non-host homologous, highly druggable
are usually considered very high value therapeutic targets. The proteins that ensure
these features are likely to have a higher rate of success. Hence, I feel these key
points need to be investigated by the authors before being considered for final consideration.
The above recommended paper should aid the authors in this endeavor.
Response 5
We recognize in depth the issues raised by the reviewers. Among the 12 proteins we
studied, there is no disordered protein structure. The three-dimensional structure
of proteins serves as an important basis for understanding their biological functions
and structure-based drug design. Using homologous mode-bonding technique, we obtained
monkeypox target protein structures based on eight (A49R, C3L, H1L, E4R, C7L, A41L,
D6L, and E13L) orthopoxviral (VAR, VAC, and CPV) proteins that were already available
as templates. As for the key proteins (A22R, I7L, C19L and A50R), which are
PONE-D-24-03917R3Identifying the core therapeutic targets of monkeypox virus and the repurposing potential
of orthopox inhibitors: an in-silico approachPLOS ONE
Dear Dr. Hu,
Thank you for submitting your manuscript to PLOS ONE. After careful consideration,
we feel that it has merit but does not fully meet PLOS ONE’s publication criteria
as it currently stands. Therefore, we invite you to submit a revised version of the
manuscript that addresses the points raised during the review process.
==============================
ACADEMIC EDITOR: Please rewrite the title of the manuscript, to avoid overlapping and similarity with
the previously published article. The title must clearly express the content of your
manuscript.
==============================
Please submit your revised manuscript by Jul 13 2024 11:59PM. If you will need more
time than this to complete your revisions, please reply to this message or contact
the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.
Please include the following items when submitting your revised manuscript:
A rebuttal letter that responds to each point raised by the academic editor and reviewer(s).
You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version.
You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload
this as a separate file labeled 'Manuscript'.
If you would like to make changes to your financial disclosure, please include your
updated statement in your cover letter. Guidelines for resubmitting your figure files
are available below the reviewer comments at the end of this letter.
We look forward to receiving your revised manuscript.
Kind regards,
Mahmoud Kandeel
Academic Editor
PLOS ONE
Journal Requirements:
Please review your reference list to ensure that it is complete and correct. If you
have cited papers that have been retracted, please include the rationale for doing
so in the manuscript text, or remove these references and replace them with relevant
current references. Any changes to the reference list should be mentioned in the rebuttal
letter that accompanies your revised manuscript. If you need to cite a retracted article,
indicate the article’s retracted status in the References list and also include a
citation and full reference for the retraction notice.
[Note: HTML markup is below. Please do not edit.]
[NOTE: If reviewer comments were submitted as an attachment file, they will be attached
to this email and accessible via the submission site. Please log into your account,
locate the manuscript record, and check for the action link "View Attachments". If
this link does not appear, there are no attachment files.]
While revising your submission, please upload your figure files to the Preflight Analysis
and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first
register as a user. Registration is free. Then, login and navigate to the UPLOAD tab,
where you will find detailed instructions on how to use the tool. If you encounter
any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
Thank you very much for your email of Major decision, regarding our manuscript Core
therapeutic targets identification for monkeypox virus and repurposing of orthopox
inhibitors：an in-silico approach (Manuscript Number: PONE-D-24-03917R1).
We would like to thank wholeheartedly the referees for their valuable and helpful
comments about our manuscript. Thanks to the reviewers for their recognition of the
research objectives, rationale and methods of the article, as well as confirming the
experimental data of the article. Suggestions on the figures and structure of the
article will also be listened to and improved upon. Our replies to reviewers’ comments
are enclosed below and in the revised version of the manuscript, we marked two parts
in red: the suggestions given by the reviewers and the contents modified by the second
reading of the article. We hope that our revised manuscript is now suitable for publication
in PLOS ONE.
Thank you to the editors for their advice on article acceptance. We have reconfirmed
PLOS-ONE's requirements for articles as well as shared code to ensure that the submitted
manuscripts are in order. Second, the funder had no role in the study design, data
collection and analysis, publication decision, or preparation of the manuscript. Additionally,
the editor mentioned a data sharing program, and we accept the editor's suggestion
that we can accept sharing of data prior to article acceptance. The editor also raised
the issue of copyright, and we were acutely aware of the importance of copyright,
so we corrected the article and removed Figure s.17. Finally, for the supporting material
we made a separate file and made sure that each information file had a legend in the
manuscript following the list of references.
Reply to Reviewer 1
In this study the authors claim to have developed a monkeypox core protein library
and a library of inhibitors targeting these core proteins. The authors have in addition
built a docking server that predicts the binding modes between the protein and the
substrate to understand the molecular dialogues between these entities. Currently
there are hardly such servers dedicated for monkeypox virus. Therefore, such an endeavor
is greatly welcome. Although the paper appears to be sound overall, I have some key
recommendations that that I think can be incorporated before the paper can be accepted
for publication.
Specific comment 1
In the methodology section method 2.1. Open reading frame (ORF), the ORF needs to
be defined more concretely. I advise the authors to have a look at the results section
(3.1 The meaning of the open reading frame (ORF) and core proteins in this study)
of the paper titled “ Identification of core therapeutic targets for Monkeypox virus
and repurposing potential of drugs against them: An in silico approach ”for better
clarity.
Response 1
I appreciate the editor's comments and I have taken the time to check out the full
article. The Open Reading Frame (ORF) serves as the beginning of the article and has
an important role in the subsequent work. In the Methods section we considered the
length of the article, so we simply explained the ORF. In response to the editor's
suggestion, we have explained this section in more detail, and the specific corrections
are as follows:
ORF is a fundamental concept in molecular bioinformatics, it is the normal nucleotide
sequence of a structural gene, the reading frame from the start codon to the stop
codon can encode a complete polypeptide chain, between which there is no stop codon
that interrupts the translation. The term open refers to the "open" region of an intact
gene used for protein translation, and reading frame refers to one of the six possibilities
for translation of a double-stranded gene sequence into amino acids. In molecular
biology, the detection of ORFs is an important step in the discovery of specific protein-coding
genes in the genome sequence, and can serve as an indicator of a potential protein-coding
gene. In our work, the acquisition of ORF mainly includes literature reading and database
research.
In addition to the suggestions for ORFs, the editors also made a suggestion to change
the title of the article to " Core therapeutic targets identification for monkeypox
virus and repurposing of orthopox inhibitors: an in-silico approach", which is more
in accordance with the content of the article. In our very first title, we targeted
the server, ignoring the fact that the article studies more on monkeypox virus and
core proteins. Seeing the editor's suggestion, we appreciate being able to identify
this issue and also think that changing the title would benefit the article more.
Specific comment 2
Similarly, the term core protein creates a lot of confusion. From the view of a genomics
researcher core protein is more closely associated with proteins that are highly conserved
across all the genomes. However, from the point of view of a classical virologist
core protein usually means the structural protein embedded on the outer membranes
that give a virus its definitive shape. Therefore, the authors should clearly mention
this in the manuscript as readers will comprise of people from multiple disciplines.
Again, I advise the authors to have a look at the results section (3.1). The meaning
of the open reading frame (ORF) and core proteins in this study) of the paper titled
“Identification of core therapeutic targets for Monkeypox virus and repurposing potential
of drugs against them: An in-silico approach” for better clarity.
Response 2
We thank the reviewers for this suggestion, and we do recognize the reviewers' suggestion
that the core proteins were improperly worded. In our work, core proteins are used
to denote potential proteins with the potential to inhibit monkeypox virus, and do
not refer to structural proteins or highly conserved proteins as mentioned by the
reviewer. In order to avoid misunderstanding, we have corrected all references to
core proteins in the article and replaced the original core proteins with potential
targets. The following are some of the corrections:
A new round of monkeypox virus has emerged in the United Kingdom since July 2022 and
rapidly swept the world. Currently, despite numerous research groups are studying
this virus and seeking effective treatments, the information on the open reading frame,
inhibitors, and potential targets of monkeypox has not been updated in time, and the
comprehension of monkeypox target ligand interactions remains a key challenge. Here,
we first summarized and improved the open reading frame information of monkeypox,
constructed the monkeypox inhibitor library and potential targets library by database
research as well as literature search, combined with advanced protein modeling technologies
(Sequence-based and AI algorithms-based homology modeling). In addition, we build
monkeypox virus Docking Server, a web server to predict the binding mode between targets
and substrate. The open reading frame information, monkeypox inhibitor library, and
monkeypox potential targets library are used as the initial files for server docking,
providing free interactive tools for predicting ligand interactions of monkeypox targets,
potential drug screening, and potential targets search. In addition, the update of
the three databases can also effectively promote the study of monkeypox drug inhibition
mechanism and provide theoretical guidance for the development of drugs for monkeypox.
In this issue, the reviewer again proposed a change in the title of the article. In
the previous comment, we clearly stated that we recognized the reviewer's title and
explained the reason for the title in the first place. Again, we thank the reviewers
for their attention to this issue.
Specific comment 3
Shared host homology is one of the biggest reasons for the failure of a drug from
reaching the bed from the bench. This often creates adverse reactions by to off-targeting
the host proteins instead. As a consequence, drugs often fail during clinical trials.
Therefore, the authors must verify that the 12 key proteins do not share homology
with human proteins beyond an allowable threshold (usually e-value of 0.0001 against
the entire set of human proteome dataset (taxid: 9606) is considered a good threshold).
The authors must provide this information in the manuscript.
Response 3
This question raised by the reviewer is very interesting and we have addressed it
with a detailed explanation. Shared host homology as an important issue that must
be considered for subsequent drug development, if the homology is too high it will
lead to poor drug selectivity, and attacking the viral cells while also harming the
host cells to a certain extent. In our article, this issue was neglected, so in the
revised manuscript, for both host and viral cells we added this part. This includes
calculation of physicochemical information of 12 proteins, sequence similarity with
human-derived proteins, VAC, VAR and CPV, detailing the host homology issue.
The three-dimensional structure of proteins is an important basis for understanding
their biological functions and for structure-based drug design [104]. With the rapid
development of structural biology, the speed of measuring protein 3D structures using
methods such as NMR, X-Ray or cryoelectronic microscopy (Cryo-EM) crystallography
has been greatly improved [39, 105]. However, the 3D structures of some proteins are
still difficult to determine due to many reasons, such as excessive molecular weight
or difficulty in crystallization. Before modeling the protein structures, we first
performed a series of physicochemical property analyses on 12 potential target sequences,
including Weight, PI, Extinction, Instability, Aliphatic and Hydrophathicity, and
compared the sequences of monkeypox with those of human origin and other orthopox
viruses (table s1). It was found that the structural domains of the proteins were
stabilized to a certain extent and could be used for subsequent studies; The sequence
similarity of all proteins except D6L was less than 60% to human, which avoided the
side effects of the drug caused by host homology. D6L, as an interleukin-18 binding
protein homologous to the host, functionally affirmed its high sequence similarity
to human proteins, a characteristic that also increased the difficulty of developing
drugs against it; finally, the sequence similarity between monkeypox virus and orthopoxvirus
was higher than 78%, proving the existence of commonality between them, and providing
an opportunity to seek possible orthopoxvirus-based drugs for the subsequent studies.
This lays a theoretical foundation for the search of possible monkeypox virus drugs
based on orthopox viruses.
For the key proteins of monkeypox, we found that eight (A49R, C3L, H1L, E4R, C7L,
A41L, D6L and E13L) could be obtained from orthopox viruses (VAR, VAC and MPV) modeled
with high sequence similarity. As for the key proteins (A22R, I7L, C19L and A50R),
which are not present in any of the orthopoxvirus genera, we chose AlphaFold2, which
is only one atomic width away from the true structure for most of the predicted protein
structures, to predict them. Notably that based on the multifaceted superiority, AlphaFold2
reaches the level of prediction observed by sophisticated instruments such as cryoelectron
microscopy, which can effectively guarantee the accuracy of the predicted structures
(Fig.2) [106]. Hence, we constructed a database of orthopoxvirus proteins with a capacity
of 45.
Table s1 Physicochemical properties of 12 potential target protein sequences and sequence
similarity to human and orthopoxvirus
Why only 12 proteins were selected as targets? Are all the 12 key proteins druggable?
The authors need to verify this information as not all proteins present highly druggable
surfaces for docking. The validity of the structures used for docking should be more
adequately demonstrated.
Response 4
We are grateful to the reviewers for raising the issue of proteins druggable, and
we will provide answers to each of the questions raised. Firstly, about the 12 target
proteins selected: in the preliminary background research, this work extensively read
all the articles (more than 1,000) on orthopox viruses since the first outbreak to
seek for key targets that might inhibit orthopox viruses. During infection, a large
number of proteins are involved in the process of virus invasion, replication, envelopment
and release, and the virus can be effectively inhibited by inhibiting these key proteins.
Based on literature research, 12 key proteins with important roles for the virus were
finally searched and identified by summarizing the studies of various infection processes.
The whole work does not involve screening proteins, but rather investigating all the
targets that have been clearly shown to be potential in studies. The second problem
is for the proteins druggable: the treatment of monkeypox is still in the exploratory
stage, and there is no specific drug that can effectively deal with it. The 12 target
proteins are all shown to be potentially druggable, and each protein is clearly described
in section 3.2 of the article, explaining why it is a potential target for monkeypox
treatment. In addition, all 12 proteins have clear docking sites, which were identified
by previous researchers through various chemical experiments, not just theoretical
descriptions. So, in response to the reviewer's question about the validity of the
docking structure I think there is no problem.
Specific comment 5
Are any of the proteins intrinsically disordered? This is a very key question that
needs answering. They are a fascinating class of proteins that lack a fixed or well-defined
three-dimensional structure in their free state. Therefore, docking against such proteins
are more challenging than what meets the eye. Therefore, physiochemical properties
like isoelectric point (pI), molecular weight, aliphatic index, instability index,
extinction co-efficient and residues accessibility of the 12 key proteins must be
examined and provided in the manuscript. This data will aid experimental biologists
to choose suitable proteins for experimental validation.
Overall, the proteins that are highly conserved, non-host homologous, highly druggable
are usually considered very high value therapeutic targets. The proteins that ensure
these features are likely to have a higher rate of success. Hence, I feel these key
points need to be investigated by the authors before being considered for final consideration.
The above recommended paper should aid the authors in this endeavor.
Response 5
We recognize in depth the issues raised by the reviewers. Among the 12 proteins we
studied, there is no disordered protein structure. The three-dimensional structure
of proteins serves as an important basis for understanding their biological functions
and structure-based drug design. Using homologous mode-bonding technique, we obtained
monkeypox target protein structures based on eight (A49R, C3L, H1L, E4R, C7L, A41L,
D6L, and E13L) orthopoxviral (VAR, VAC, and CPV) proteins that were already available
as templates. As for the key proteins (A22R, I7L, C19L and A50R), w
PONE-D-24-03917R4Core therapeutic targets identification for monkeypox virus and repurposing of orthopox
inhibitors: an in-silico approachPLOS ONE
Dear Dr. Hu,
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Dear dr Hu
Please resubmit your article using the initial title used during the first submission
Best regards
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PONE-D-24-03917R5Development of mechanism‐based inhibitor against Monkeypox virus: A WEB to predict
the binding patternsPLOS ONE
Dear Dr. Hu,
Thank you for submitting your manuscript to PLOS ONE. After careful consideration,
we feel that it has merit but does not fully meet PLOS ONE’s publication criteria
as it currently stands. Therefore, we invite you to submit a revised version of the
manuscript that addresses the points raised during the review process.
Please submit your revised manuscript by Sep 14 2024 11:59PM. If you will need more
time than this to complete your revisions, please reply to this message or contact
the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.
Please include the following items when submitting your revised manuscript:
A rebuttal letter that responds to each point raised by the academic editor and reviewer(s).
You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version.
You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload
this as a separate file labeled 'Manuscript'.
If you would like to make changes to your financial disclosure, please include your
updated statement in your cover letter. Guidelines for resubmitting your figure files
are available below the reviewer comments at the end of this letter.
We look forward to receiving your revised manuscript.
Kind regards,
Milad Zandi, Ph.D.
Academic Editor
PLOS ONE
Journal Requirements:
Please review your reference list to ensure that it is complete and correct. If you
have cited papers that have been retracted, please include the rationale for doing
so in the manuscript text, or remove these references and replace them with relevant
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Reviewers' comments:
Reviewer's Responses to Questions
Comments to the Author
1. If the authors have adequately addressed your comments raised in a previous round
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may indicate that here to bypass the “Comments to the Author” section, enter your
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your "Accept" recommendation.
Reviewer #3: All comments have been addressed
Reviewer #4: (No Response)
**********
2. Is the manuscript technically sound, and do the data support the conclusions?
The manuscript must describe a technically sound piece of scientific research with
data that supports the conclusions. Experiments must have been conducted rigorously,
with appropriate controls, replication, and sample sizes. The conclusions must be
drawn appropriately based on the data presented.
Reviewer #3: Yes
Reviewer #4: Yes
**********
3. Has the statistical analysis been performed appropriately and rigorously?
Reviewer #3: Yes
Reviewer #4: Yes
**********
4. Have the authors made all data underlying the findings in their manuscript fully
available?
The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript
fully available without restriction, with rare exception (please refer to the Data
Availability Statement in the manuscript PDF file). The data should be provided as
part of the manuscript or its supporting information, or deposited to a public repository.
For example, in addition to summary statistics, the data points behind means, medians
and variance measures should be available. If there are restrictions on publicly sharing
data—e.g. participant privacy or use of data from a third party—those must be specified.
Reviewer #3: Yes
Reviewer #4: Yes
**********
5. Is the manuscript presented in an intelligible fashion and written in standard
English?
PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles
must be clear, correct, and unambiguous. Any typographical or grammatical errors should
be corrected at revision, so please note any specific errors here.
Reviewer #3: Yes
Reviewer #4: Yes
**********
6. Review Comments to the Author
Please use the space provided to explain your answers to the questions above. You
may also include additional comments for the author, including concerns about dual
publication, research ethics, or publication ethics. (Please upload your review as
an attachment if it exceeds 20,000 characters)
Reviewer #3: The article provides a detailed introduction on monkeypox, summarises and refines
the open reading frame information of monkeypox, and constructs a model of monkeypox
target-ligand interactions. In addition, a monkeypox virus docking server, which is
a web server for predicting the binding mode of targets and substrates, was constructed,
which is conducive to the further advancement of monkeypox virus drug screening and
target identification. The amount of data in the article is sufficient, the analysis
is reasonable and there are no ethical issues, I recommend plos one to receive the
manuscript.
Reviewer #4: In this study the authors claim to have developed a monkeypox core protein library
and a library of inhibitors targeting these core proteins. The authors have in addition
built a docking server that predicts the binding modes between the protein and the
substrate to understand the molecular dialogues between these entities. Currently
there are hardly such servers dedicated for monkeypox virus. Therefore, such an endeavor
is greatly welcome. While the paper as a whole looks good, I have a few tips that
I think need to be explained before the paper is accepted for publication.
1.Why only 12 proteins were selected as targets? Are all the 12 key proteins druggable?
The authors need to verify this information as not all proteins present highly druggable
surfaces for docking. The validity of the structures used for docking should be more
adequately demonstrated.
2.Given that a significant portion of the protein crystal structures remains unresolved,
the authors generated homology models to address this limitation. How did the authors
predict the orthosteric sites of the protein targets? Was a validation conducted against
known inhibitors to assess the accuracy of the predicted orthosteric sites?
3.The manuscript title can also be improved. It does not resonate with the work done
or the core feature of the server.
**********
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(what does this mean?). If published, this will include your full peer review and any attached files.
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be made public.
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Reviewer #3: No
Reviewer #4: No
**********
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While revising your submission, please upload your figure files to the Preflight Analysis
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any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.
Thank you very much for your email of Major decision, regarding our manuscript Development
of mechanism‐based inhibitor against Monkeypox virus: A WEB to predict the binding
patterns (Manuscript Number: PONE-D-24-03917R1).
We would like to thank wholeheartedly the referees for their valuable and helpful
comments about our manuscript. Thanks to the reviewers for their recognition of the
research objectives, rationale and methods of the article, as well as confirming the
experimental data of the article. Suggestions on the figures and structure of the
article will also be listened to and improved upon. Our replies to reviewers’ comments
are enclosed below and in the revised version of the manuscript, we marked two parts
in red: the suggestions given by the reviewers and the contents modified by the second
reading of the article. We hope that our revised manuscript is now suitable for publication
in PLOS ONE.
The article provides a detailed introduction on monkeypox, summarises and refines
the open reading frame information of monkeypox, and constructs a model of monkeypox
target-ligand interactions. In addition, a monkeypox virus docking server, which is
a web server for predicting the binding mode of targets and substrates, was constructed,
which is conducive to the further advancement of monkeypox virus drug screening and
target identification. The amount of data in the article is sufficient, the analysis
is reasonable and there are no ethical issues, I recommend plos one to receive the
manuscript.
Reviewer #4:
In this study the authors claim to have developed a monkeypox core protein library
and a library of inhibitors targeting these core proteins. The authors have in addition
built a docking server that predicts the binding modes between the protein and the
substrate to understand the molecular dialogues between these entities. Currently
there are hardly such servers dedicated for monkeypox virus. Therefore, such an endeavor
is greatly welcome. While the paper as a whole looks good, I have a few tips that
I think need to be explained before the paper is accepted for publication.
Specific comment 1
Why only 12 proteins were selected as targets? Are all the 12 key proteins druggable?
The authors need to verify this information as not all proteins present highly druggable
surfaces for docking. The validity of the structures used for docking should be more
adequately demonstrated.
Response 1
We are grateful to the reviewers for raising the issue of proteins druggable, and
we will provide answers to each of the questions raised. Firstly, about the 12 target
proteins selected: in the preliminary background research, this work extensively read
all the articles (more than 1,000) on orthopox viruses since the first outbreak to
seek for key targets that might inhibit orthopox viruses. During infection, a large
number of proteins are involved in the process of virus invasion, replication, envelopment
and release, and the virus can be effectively inhibited by inhibiting these key proteins.
Based on literature research, 12 key proteins with important roles for the virus were
finally searched and identified by summarizing the studies of various infection processes.
The whole work does not involve screening proteins, but rather investigating all the
targets that have been clearly shown to be potential in studies. The second problem
is for the proteins druggable: the treatment of monkeypox is still in the exploratory
stage, and there is no specific drug that can effectively deal with it. The 12 target
proteins are all shown to be potentially druggable, and each protein is clearly described
in section 3.2 of the article, explaining why it is a potential target for monkeypox
treatment. In addition, all 12 proteins have clear docking sites, which were identified
by previous researchers through various chemical experiments, not just theoretical
descriptions. So, in response to the reviewer's question about the validity of the
docking structure I think there is no problem.
Specific comment 2
Given that a significant portion of the protein crystal structures remains unresolved,
the authors generated homology models to address this limitation. How did the authors
predict the orthosteric sites of the protein targets? Was a validation conducted against
known inhibitors to assess the accuracy of the predicted orthosteric sites?
Response 2
Thanks to the reviewers for their professional advice. Proteins are important functional
molecules in living organisms, and their structures determine their functions and
interaction modes. Accurate three-dimensional structures of proteins are of key significance
in revealing their biological functions, disease mechanisms, and drug development.
In our work, the monkeypox virus protein structure was targeted mainly by template-based
homology modal bonding and sequence-based modal bonding. Discovery Studio program
(DS), as a professional molecular simulation software for life sciences, has been
used in the characterization of proteins (including protein-protein interactions),
homology modeling, molecular mechanics calculations and molecular dynamics simulations,
structure-based drug design tools ( including ligand-protein interactions, novel drug
design and molecular docking), small-molecule-based drug design tools (including quantitative
conformational relationships, pharmacophore, database screening, ADMET), and design
and analysis of combinatorial libraries. By using DS, a reasonable protein structure
can be well obtained based on amino acid sequence mode bonds with certain sequence
similarity, and this technique is also widely used and verified to be reasonable by
major groups. For the sequence similarity content of protein structures, we have also
made corresponding additions to demonstrate the high sequence similarity among orthopox
viruses and the rationality of obtaining structures through homologous mold bonds.
Here we give some literature on the use of the program to die bond protein structures
in order to open the work: Studio D. Accelrys, 2008, 420; Evers A, Klebe G. Journal
of medicinal chemistry, 2004, 47(22): 5381-5392; Duan H, Hu K, Zheng D, et al. International
Journal of Biological Macromolecules, 2022, 223: 1562-1577. For protein structures
without templates, we chose the AlphaFold2 technique, which has gained more recognition
in recent years. As a deep machine learning method, AlphaFold2 achieves an average
accuracy of 92.4 for predicting proteins from scratch, which is almost comparable
to experimentally resolved structures. Using the AlphaFold2 technique, we selected
the highest scoring structures as rational structures and used them for subsequent
drug screening work. In addition, the reviewer asked how to predict the orthosteric
site of the protein and whether to verify the site with inhibitors. We thank the reviewers
for asking this question again, and we understand that the orthosteric site is the
active site that exerts binding to the substrate. In the previous question we explained
that all binding sites were obtained experimentally and not by molecular modeling
techniques. For the active site validation problem, we also gave a detailed explanation
in the third question and corrected the content of the main text. The docking results
showed that more than 68% of the compounds in the small molecule library were successfully
bound to the correct site, which proves the accuracy of the active site from the side.
Specific comment 3
The manuscript title can also be improved. It does not resonate with the work done
or the core feature of the server.
Response 3
Regarding the manuscript title issue. We thank the reviewer for raising this issue,
and we have also adjusted the title of the manuscript based on summarizing the full
text, and the new title is entitled: Identification of core therapeutic targets for
Monkeypox virus and repurposing potential of drugs: A WEB prediction approach.
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Academic Editor
PLOS ONE
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Reviewer #3: All comments have been addressed
Reviewer #4: All comments have been addressed
**********
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The manuscript must describe a technically sound piece of scientific research with
data that supports the conclusions. Experiments must have been conducted rigorously,
with appropriate controls, replication, and sample sizes. The conclusions must be
drawn appropriately based on the data presented.
Reviewer #3: Yes
Reviewer #4: Yes
**********
3. Has the statistical analysis been performed appropriately and rigorously?
Reviewer #3: Yes
Reviewer #4: N/A
**********
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available?
The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript
fully available without restriction, with rare exception (please refer to the Data
Availability Statement in the manuscript PDF file). The data should be provided as
part of the manuscript or its supporting information, or deposited to a public repository.
For example, in addition to summary statistics, the data points behind means, medians
and variance measures should be available. If there are restrictions on publicly sharing
data—e.g. participant privacy or use of data from a third party—those must be specified.
Reviewer #3: Yes
Reviewer #4: Yes
**********
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English?
PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles
must be clear, correct, and unambiguous. Any typographical or grammatical errors should
be corrected at revision, so please note any specific errors here.
Reviewer #3: Yes
Reviewer #4: Yes
**********
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Please use the space provided to explain your answers to the questions above. You
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in its current format.
**********
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