A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study

Alireza Mohebbi; Touba Ghorbanzadeh; Shabnam Naderifar; Fattaneh Khalaj; Fatemeh Sana Askari; Ali Salehnia Sammak

doi:10.1371/journal.pone.0285941

Peer Review History

Original SubmissionNovember 17, 2022
31 Jan 2023 Decision Letter - Pramodkumar Pyarelal Gupta, Editor PONE-D-22-31671A Fragment-based drug discovery developed on Ciclopirox for inhibition of Hepatitis B virus core protein: An in silico studyPLOS ONE Dear Dr. Mohebbi, 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 Mar 17 2023 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. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Pramodkumar Pyarelal Gupta, PhD Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. Additional Editor Comments: It seems the compound is not much big and very less fragment is possible hence the author should report the fragments, which will validate study. What is mean ΔGB? And its significance. Whether these all fragments are tested on same biological targets or some correlation? Do the authors are working on QSAR model or SAR model? In QSAR model what were the dependent and independent variables? In discussion part the authors should discuss with the similar case. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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 #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. 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 #1: No ****** 4. 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 #1: Yes ****** 5. 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 #1: Interesting piece of work showing some new arenas for drug repurposing w.r.t Hepatitis B virus. However, I feel incorporation of a few changes might enhance the manuscript. 1. Interchanging paragraph 2 (49-57) and paragraph 3 (58-66):. Paragraph 1 and 3 talks about structure of the virus, while paragraph 2 and 4 talks about the drugs and treatments against the virus. Bringing paragraph 3 in place of paragraph 2 will make the introduction of Hepatitis B Virus seamless. 2. Not much has been written about Ciclopirox in the introduction and would suggest addition of a few more lines regarding Ciclopirox. 3. Comparison of the binding affinity of the target to a positive control will help in understanding of the efficacy of the drug fragment. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** [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. https://doi.org/10.1371/journal.pone.0285941.r001
Revision 1
9 Mar 2023 Author Response March 9, 2023 To: Editorial of PONE; Thanks to the reviewer and editorials for their suggestions for improving the presentation of our paper, the comments and rephrases are presented in the revised manuscript. We hope that the revised version of the manuscript be more strengthened in details. Here, the comments of the reviewers and the editorial are addressed and also revised in the text. 1. Journal Requirements: Authors response and action: The MS revised according to the template file. The Data Availability statement is updated by addition of the raw data file including all used information and statistics within the study. The figures were also revised in PACE server. 2. Additional Editor Comments: 1. It seems the compound is not much big and very less fragment is possible hence the author should report the fragments, which will validate study. Author response and action: You are right, the derivatives are very small. We have revised the MS to describe the cause of smallness of the derivatives. Since the crystallographic structure of HBcAg complexed with Ciclopirox was used for FBDD, the resulted derivatives in the same binding site were small due to addition of fewer potent fragments inferring more suitable ∆GB affinities (Discussion section lines 208-210). 2. What is mean ΔGB? And its significance. Author response and action: ΔGB was the free energy of binding, and we have revised it in the MS in the Fragment-based drug discovery sub-heading in M&M (lines 106-106). We have used the values of ΔGB for ranking the ligands. 3. Whether these all fragments are tested on same biological targets or some correlation? Author response and action: Thank you so much for the comment. We have only tested the fragments on a same target (HBcAg) in silico. 4. Do the authors are working on QSAR model or SAR model? Author response and action: It is working on QSAR model. Therefore, we have revised it through the MS. 5. In QSAR model what were the dependent and independent variables? Author response and action: The affinity of the training and test sets were used as the dependent variable, and the chemical descriptors were set as the independent variables. This also mentioned and revised in the M&M section, subheading “Quantitative structure affinity relationship (QSAR)” 6. In discussion part the authors should discuss with the similar case. Author response and action: We have discussed a similar paper in which the researchers developed Ciclopirox analogs for inhibiting the replication of human Herpes viruses (Lines 204-206). 3. Reviewers' comments: Reviewer #1: Interesting piece of work showing some new arenas for drug repurposing w.r.t Hepatitis B virus. However, I feel incorporation of a few changes might enhance the manuscript. 1. Interchanging paragraph 2 (49-57) and paragraph 3 (58-66):. Paragraph 1 and 3 talks about structure of the virus, while paragraph 2 and 4 talks about the drugs and treatments against the virus. Bringing paragraph 3 in place of paragraph 2 will make the introduction of Hepatitis B Virus seamless. Author response and action: AS recommended by dear review, P3 brought prior to the P2 in the revised MS. 2. Not much has been written about Ciclopirox in the introduction and would suggest addition of a few more lines regarding Ciclopirox. Author response and action: As correctly recommended by the reviewer, more sentences is now added to the MS describing more about Ciclopirox. The revision lies in the last paragraph of the Introduction section (lines 85-88). 3. Comparison of the binding affinity of the target to a positive control will help in understanding of the efficacy of the drug fragment. Author response and action: Thank you so much for the comment. Ciclopirox was used as the positive control with the same binding site and also its affinity to the HBcAg was chosen as the cut-off value for selecting efficient ligands. This is revised in the first paragraph, and highlighted in yellow. Again, we are very grateful for considering our manuscript for peer-review. We hope the current version of the manuscript considered for publication in PONE. Kind regards Alireza Mohebbi Ph.D. candidate in Medical Virology, Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran E-mail: Mohebbi-a@goums.ac.ir Tel: +98 9354674593 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0285941.r002
5 May 2023 Decision Letter - Pramodkumar Pyarelal Gupta, Editor A Fragment-based drug discovery developed on Ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study PONE-D-22-31671R1 Dear Dr. Mohebbi, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Pramodkumar Pyarelal Gupta, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): NA 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 of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 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 #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 #1: 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 #1: 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 #1: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0285941.r003
Formally Accepted
8 May 2023 Acceptance Letter - Pramodkumar Pyarelal Gupta, Editor PONE-D-22-31671R1 A fragment-based drug discovery developed on ciclopirox for inhibition of Hepatitis B virus core protein: An in silico study Dear Dr. Mohebbi: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Pramodkumar Pyarelal Gupta Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0285941.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .