RETRACTED: Application of in-silico drug discovery techniques to discover a novel hit for target-specific inhibition of SARS-CoV-2 Mpro’s revealed allosteric binding with MAO-B receptor: A theoretical study to find a cure for post-covid neurological disorder

Magdi E. A. Zaki; Sami A. AL-Hussain; Aamal A. Al-Mutairi; Abdul Samad; Vijay H. Masand; Rahul G. Ingle; Vivek Digamber Rathod; Nikita Maruti Gaikwad; Summya Rashid; Pravin N. Khatale; Pramod V. Burakale; Rahul D. Jawarkar

doi:10.1371/journal.pone.0286848

Peer Review History

Original SubmissionMarch 22, 2023
24 Apr 2023 Decision Letter - Arabinda Ghosh, Editor PONE-D-23-08644Application of In Silico Drug Discovery Techniques to Discover a Novel Hit for Target-Specific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric binding with MAO-B receptor: A theoretical study to Find a cure for post Covid Neurological disorderPLOS ONE Dear Dr. Jawarkar, 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 Jun 08 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. 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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 Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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: Yes Reviewer #2: Yes ****** 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 Reviewer #2: 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: The manuscript entitled “Application of In Silico Drug Discovery Techniques to Discover a Novel Hit for TargetSpecific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric binding with MAO-B receptor: A theoretical study to Find a cure for post Covid Neurological disorder” relies on in silico techniques to identify novel lead candidates that exhibit interactions with SARS-CoV-2 Mpro and MAO-B of a set 106 molecules obtained from literature. The paper included variety of computational methods, including QSAR analysis, QSAR-based virtual screening, molecular docking, drug re-purposing, molecular dynamics (MD) simulation, and molecular mechanics. However, in order to meet the satisfaction criteria for publication of this work in the PLOS ONE, several remarks were considered such as: Please see attached file Reviewer #2: MS by Zaki et al. entitled ‘Application of In Silico Drug Discovery Techniques to Discover a Novel Hit for Target-Specific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric binding with MAO-B receptor: A theoretical study to Find a cure for post Covid Neurological disorder’ is a good piece of information and I find this article interesting. However, I have below suggestions: # Abstractc written is bit long and authors are supposed to write in a very short way. # Dataset splitting with 50: 50 should not be used herein. It should be 70:30 %. Authors are advised to refer and follow recent articles DOI: 10.1080/07391102.2023.2190803; DOI: 10.1142/S2737416522500387; DOI: 10.1038/s41598-022-20325-1. # At line 757, I suggest to use subscript for abbreviations of contributing energies. # Figures 12-14 should be replaced with high resolution images. At current state they are unable to check for their legends. # Overall, I suggest MS acceptance following aforementioned changes and citations. ****** 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. 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Attachments Attachment Submitted filename: Report - PONE.docx https://doi.org/10.1371/journal.pone.0286848.r001
Revision 1
10 May 2023 Author Response Point to Point Response to Reviewers Comments Reviewer#1 The manuscript entitled “Application of In Silico Drug Discovery Techniques to Discover a Novel Hit for Target Specific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric Binding with MAO-B Receptor: A theoretical study to Find a Cure for post Covid Neurological Disorder” relies on in silico techniques to identify novel lead candidates that exhibit interactions with SARS-CoV-2 Mpro and MAO-B of a set 106 molecules obtained from the literature. The paper included a variety of computational methods, including QSAR analysis, QSAR-based virtual screening, molecular docking, drug re-purposing, molecular dynamics (MD) simulation, and molecular mechanics. However, in order to meet the satisfaction criteria for publication of this work in PLOS ONE, several remarks were considered such as: 1- Authors should rewrite the abstract and the conclusion concisely, it’s very long. Response: Thank you very much for your comment. As per the suggestion, we have concise the abstract for better clarity and readability. 2- The authors should reformulate the titles for figures and tables Response: Please accept my sincere gratitude for your insightful feedback. All of the table and figure names in the text have been updated following your suggestion. 3- What is the purpose behind using both the QSAR virtual screening and QSAR GA-MLR? Please explain. Response: Thank you very much for your insightful comment. The GA-MLR is a genetic algorithm multilinear regression analysis. Multiple linear regression is a statistical approach that employs multiple linear regression to describe more complicated interactions between two or more independent variables and one dependent variable. The genetic algorithm was used along with multiple linear regression used for variable selection in multivariable regression models. In contrast, the QSAR-based virtual screening predicts the bioactivity of the compounds in any database or chemical library using a QSAR model developed using specific statistical techniques like GA-MLR, PLS, etc. Reference: David Broadhurst, Royston Goodacre, Alun Jones, Jem J Rowland, Douglas B Kell, Genetic algorithms as a method for variable selection in multiple linear regression and partial least squares regression, with applications to pyrolysis mass spectrometry, Analytica Chimica Acta, Volume 348, Issues 1–3, 1997, Pages 71-86, 4- Which criteria are used to divide the dataset into training and validation sets? Response: Thank you very much for your interesting comment. With all due respect, datasets are divided into training and test sets either randomly, or by an activity-range algorithm. We have included reference no 51 in the manuscript to justify the criteria to divide the dataset into training and test set. Reference: O.A. Raevsky, V.Yu. Grigor’ev, E.E. Weber, and J.C. Dearden, Classification and quantification of the toxicity of chemicals to guppy, fathead minnow and rainbow trout: Part 1. Nonpolar narcosis mode of action, QSAR Comb. Sci. 27 (2008), pp. 1274–1281. 5- The Material and Methods section should provide information about the material used and adopted practical procedures and steps to acquire the results without listing results or discussion-like text. The authors should have defined and explained the used methods in this work for readers who are not familiar with the methods and applications to understand. The information included on the different modeling techniques is quite trivial and should be omitted and replaced by relevant references. Response: Thank you very much for your valuable comment and insightful suggestion. As per the comment, we have modified the sequence of manuscript content in the following order for better clarity and readability. The modified sequence is; 1) Introduction, 2) Material and Method, 3) Results, 4) Discussion, and 5) Conclusion 6- It is evident that there are many other structural and non-structural protein targets associated with the SARS-CoV-2 Mpro and MAO-B proteins available in PDB and hence authors limited their research to only one target (6lu7 for Mpro and 2v61 for MAO-B) without an explanation of why should selected compounds target precisely that target. Response: Thank you very much for your insightful comment. With all due respect, the pdb: 6lu7 was co-crystallized with the ligand and showed a low resolution of 2.16 Å with the completion of the amino acid sequence. Moreover, the pdb:6li7 was used in the following references; DOI: https://dx.doi.org/10.22159/ijap.2022v14i1.43132, doi: 10.1016/j.molstruc.2020.129230, https://doi.org/10.1016/j.sjbs.2021.10.060, https://doi.org/10.1021/acs.jcim.0c00283, https://doi.org/10.1007/s42250-021-00296-y, https://doi.org/10.1038/s41598-020-74468-0. Based on this we have selected pdb:6lu7. • On the other hand, we have employed the same criteria like; as the occurrence of pdb with co-crystallized ligand with the completion of the amino acid sequence., and a resolution of 1.70 Å for the selection of MAO-B pdb 2v61. Furthermore, the pdb 2v61 was reported in various renowned literatures such as; DOI: 10.15436/2575-808X.17.1356, doi: 10.1021/acs.jmedchem.8b00204, https://doi.org/10.1021/acs.jmedchem.8b00204, 7- Provide details of the docking protocol and parameters, including the algorithm scoring function. It is necessary to mention whether the entire receptor was kept rigid, or if some side chains were treated flexibly. The exhaustiveness, and number of binding modes generated need to be mentioned. Mention the grid size, grid spacing, and grid center for docking. Response: Thank you very much for your constructive comment. We bring to your kind attention that, the NRGsuite uses a different algorithm and protocol different from the AutoDock software. In the NRG suite, the active site is selected using the sphere (radius 5Å in the present work) with the center at the center of the active site. Al residues within this sphere are automatically considered flexible by the software. The software then uses a genetic algorithm to generate thousands of conformations of ligands to identify the best docking pose. 8- There is confusion in the text, the authors many times talk about compound 4 and sometimes compound 47, if it’s similar correct it, if not what does represent compound 4? Response: Thank you very much for point our mistake. As per the comment, we have included a uniform abbreviation of compound 4 (ZINC ID: 32719065) throughout the entire manuscript. The changes are highlighted in yellow color. 9- In Figure 6, the authors must redraw the structure of molecule 3 as the format of the other molecules Response: Thank you very much for your valuable suggestion. As per the suggestion, we have added a new redrawn structure of compound 3 in Figure 6 for better clarity. 10- In lines 213 and 214, there is a redundancy that must be corrected. Response: Thank you very much for pointing out our mistake. As per the comment, we have modified the entire sentence for better clarity and readability. The changes are highlighted by yellow color. 11- In Figure 4, the authors must correct in the first molecule 4 by 3. Response: Thank you very much for pointing out our mistake. As per your valuable comment, we have modified Figure 4 and replaced 4 with 3. The changes are highlighted in yellow color. 12- In Figure 3, the graph plotted is for which model 1 or 2, please precise, and why not the results of both models are represented? Response: Thank you very much for your valuable comment. As per the comment, graph 2 belongs to model 1, while model 2 graphs are presented in Figure 3. 13- In line 178, the author should add in for which model, “supplementary table S3 for the model..” Response: Thank you very much for highlighting our mistake. By mistake, we haven’t added table S3 for model 2. As per your valuable suggestion. We have added the supplementary material for model 2. The changes are highlighted in yellow color. 14- Which software was used for energy minimization of the three-dimensional structures? Response: Thank you very much for your insightful comment. As per the comment, we have used open Babel software energy minimization using MMFF94 forcefield while conversion of structures from 2D to 3D. In support of this, we have already added references no 47 and 48. On the other hand, while in molecular docking, we have used UCSF Chimera software for energy minimization of target compound 4. The changes are highlighted in yellow color. 15- How did you confirm the protein structure quality by using the Ramachandran plot? Please add the plot to the manuscript Response: Thank you very much for the insightful comment. The high resolution of protein 6lu7 and the existence of ligand in the active site, which is present almost on the periphery of the protein structure could be the reason for the high similarity of the Ramachandran plot for before and after optimization. As per the comment, we have added the Ramachandran plot for the pdb 6lu7. 16- Authors should properly discuss and compare their results. I recommend some papers which the author should read and follow while writing: https://doi.org/10.1007/s11224-022-02004-z https://doi.org/10.1016/j.molstruc.2022.132652 https://doi.org/10.1016/j.jksus.2022.102226 https://doi.org/10.1016/j.compbiomed.2021.104758 https://doi.org/10.1080/07391102.2021.1957712 https://doi.org/10.1016/j.jksus.2021.101352 https://doi.org/10.1080/07391102.2021.1914170 https://doi.org/10.1007/s11224-022-01939-7 Response: Thank you very much for suggesting such a nice reference. Reviewer#2 Reviewer #2: MS by Zaki et al. entitled ‘Application of In Silico Drug Discovery Techniques to Discover a Novel Hit for Target-Specific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric Binding with MAO-B receptor: A theoretical study to Find a cure for post-Covid Neurological disorder’ is a good piece of information and I find this article interesting. However, I have below suggestions: # Abstractc written is a bit long and authors are supposed to write in a very short way. Response: Thank you very much for your valuable suggestion. As per the suggestion, we have concise the abstract for better clarity and readability. The changes are highlighted by yellow color. # Dataset splitting with 50: 50 should not be used herein. It should be 70:30 %. Authors are advised to refer and follow recent articles DOI: 10.1080/07391102.2023.2190803; DOI: 10.1142/S2737416522500387; DOI: 10.1038/s41598-022-20325-1. Response: Thank you very much for your valuable suggestion. The dataset splitting was done 50:50 to capture the maximum information and avoid any bias. The strategy has been well explained in the following paper; https://doi.org/10.1016/j.molstruc.2018.07.080, http://dx.doi.org/10.1016/j.ejps.2015.06.001. Thank you very much for suggesting such good references. # At line 757, I suggest using subscript for abbreviations of contributing energies. Response: Thank you very much for your valuable suggestion. As per the comment, we have added subscripts for abbreviations of contributing energies. The changes are highlighted in yellow color. # Figures 12-14 should be replaced with high resolution images. At current state they are unable to check for their legends. Response: Thank you very much for your valuable suggestion. As per the suggestion, we have changed figures 12-14 with high-resolution images. # Overall, I suggest MS acceptance following the aforementioned changes and citations. Response: Thank you very much for appreciating our work. Attachments Attachment Submitted filename: R1_Response to Reviewer comments.docx https://doi.org/10.1371/journal.pone.0286848.r002
24 May 2023 Decision Letter - Arabinda Ghosh, Editor Application of In Silico Drug Discovery Techniques to Discover a Novel Hit for Target-Specific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric binding with MAO-B receptor: A theoretical study to Find a cure for post Covid Neurological disorder PONE-D-23-08644R1 Dear Dr. Jawarkar, 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, Arabinda Ghosh Academic Editor PLOS ONE Additional Editor Comments (optional): 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 Reviewer #2: 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: All comments have been adressed. This paper can be published in the current form in the PLOS ONE journal Reviewer #2: Dear Editor, Authors have clarified all my queries. Authors have addressed all minimum requirements as assigned. ****** 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: Yes: Professor Samir Chtita Reviewer #2: Yes: Dr. Anima Pandey ******** https://doi.org/10.1371/journal.pone.0286848.r003
Formally Accepted
13 Jun 2023 Acceptance Letter - Arabinda Ghosh, Editor PONE-D-23-08644R1 Application of In-Silico Drug Discovery Techniques to Discover a Novel Hit for Target-Specific Inhibition of SARS-CoV-2 Mpro's Revealed Allosteric Binding with MAO-B Receptor: A theoretical study to Find a Cure for post-Covid Neurological Disorder Dear Dr. Jawarkar: 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. Arabinda Ghosh Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0286848.r004

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