Identification of novel cyclin-dependent kinase 4/6 inhibitors from marine natural products

Abhijit Debnath; Rupa Mazumder; Anil Kumar Singh; Rajesh Kumar Singh

doi:10.1371/journal.pone.0313830

Peer Review History

Original SubmissionSeptember 1, 2024
29 Sep 2024 Decision Letter - Ahmed A. Al-Karmalawy, Editor PONE-D-24-38269Identification of Novel Cyclin-dependent kinase 4/6 Inhibitors from Marine Natural ProductsPLOS ONE Dear Dr. Debnath, 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 Nov 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. 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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: N/A 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: No 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 paper is well presented and the data is well written. My only comment would be to make sure the figures are cleaner. For example, Fig 3 has the labels pf the different rankings overlapped with the outer circle, and Fig 9 and 11 have the box with the legends in transparent, that causes it to overlap with the grid lines on the plot. Reviewer #2: The study presented provides in silico approach to screen CDK 4/6 inhibitors, while the study and analysis is useful and could be considered for publication, but it needs some corrections. General Comments: 1) The Introduction section seems non-coherent and should be reorganized. For example, some statements have been repeated and are redundant. Acronyms should be defined whenever they are occuring for the first time in the introduction for readers. 2) Authors should put more emphasis on why marine-based compounds were chosen. Also, was all 9497 identified compounds are marine based? 3) What are color attributes in Table 1 and 2 for consensus molecular docking? 4) Did authors determined protonation states of the CDK4/6 complex?? 5) Authors mentioned they simulated 100 ns at physiological conditions. I am rather confused what conditions were used for other 400 ns?? 6) Did authors simulated protein in apo state? 7) Kcal/Mol should be changed to kcal/mol (small caps) 8) RMSD plots show the RMSD of the system increases after 400 ns. Would authors comment on this? 9) RMSF figure should be replotted to match the y-axes. 10) How key residues were chosen for RMSF analysis? Why residues 170-180 shows higher RMSF, why they are none of the residues are in key residues? What role these residues play in binding? 11) How the "key residues" were identified. 12) The authors should put cell viability plots? 13) From my understanding authors study aimed to target triple negative breast cancer. Whereas MCF-7 is not triple negative. Would author comment on why MCF-7 cell line was chosen, or should clarify it in the introduction. 14) The text in some plots in too small to be readable. Authors are suggested to increase the font size to improve readability. ****** 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 Reviewer #2: 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.0313830.r001
Revision 1
4 Oct 2024 Author Response Reviewer # 1: The paper is well presented and the data is well written. My only comment would be to make sure the figures are cleaner. Problem 1: For example, Fig 3 has the labels pf the different rankings overlapped with the outer circle, and Fig 9 and 11 have the box with the legends in transparent, that causes it to overlap with the grid lines on the plot. Reply 1: We have updated the representation of Fig 3, 9 and 11 as per suggestion. Reviewer # 2: The study presented provides in silico approach to screen CDK 4/6 inhibitors, while the study and analysis is useful and could be considered for publication, but it needs some corrections. General Comments: Problem 1: The Introduction section seems non-coherent and should be reorganized. For example, some statements have been repeated and are redundant. Acronyms should be defined whenever they are occuring for the first time in the introduction for readers. Reply 1: We have updated the “Introduction” section as per your suggestion. Problem 2: Authors should put more emphasis on why marine-based compounds were chosen. Also, was all 9497 identified compounds are marine based? Reply 2: Yes, in the updated “Introduction” Section, we have given more emphasis on why marine-based compounds were chosen. Yes The CMNPD database [36], and MNP library [37] both consist of marine-based compounds, thus 9497 identified compounds are marine-based. Problem 3: What are color attributes in Table 1 and 2 for consensus molecular docking? Reply 3: A color gradient from cool (blue) to warm (red) colors is used to visually represent the docking scores, with cooler colors indicating more negative (favorable) binding energies and warmer colors indicating less favorable binding energies. We have updated in the manuscript too. Problem 4: Did authors determined protonation states of the CDK4/6 complex?? Reply 4: Yes , we did it. Problem 5: Authors mentioned they simulated 100 ns at physiological conditions. I am rather confused what conditions were used for other 400 ns??. Reply 5: We have corrected it. Problem 6: Did authors simulated protein in apo state? Reply 6: Yes Problem 7: Kcal/Mol should be changed to kcal/mol (small caps) Reply 7: We have corrected it. Problem 8: RMSD plots show the RMSD of the system increases after 400 ns. Would authors comment on this? Reply 8: Yes, few of them have shown such tendencies probably due to alternative binding mode, we have screened out only those molecules which formed stable complexes. Problem 9: RMSF figure should be replotted to match the y-axes. Reply 9: We have corrected as per suggestion. Problem 10: How key residues were chosen for RMSF analysis? Why residues 170-180 shows higher RMSF, why they are none of the residues are in key residues? What role these residues play in binding? Reply 10: Yes, residues 170-180 shows higher RMSF as because these region is the loop region. Moreover, these regions do not fall in the active site, it is far away from the active site, thus the role these residues play in binding is minimal. Problem 11: How the "key residues" were identified. Reply 11: In the section “2.1.1 Active Site” we have mentioned that binding site residues of the CDK4/6 complex were elucidated through a comprehensive analysis of previously published literature [31–33] and further validated through computational tools CASTp [34] as well as AADS[35]. Problem 12: The authors should put cell viability plots? Reply 12: We have added and updated the manuscript. Problem 13: From my understanding authors study aimed to target triple negative breast cancer. Whereas MCF-7 is not triple negative. Would author comment on why MCF-7 cell line was chosen, or should clarify it in the introduction. Reply 13: We have corrected and updated the manuscript accordingly Problem 14: The text in some plots in too small to be readable. Authors are suggested to increase the font size to improve readability. Reply 14: We have updated and corrected the plots accordingly. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0313830.r002
21 Oct 2024 Decision Letter - Ahmed A. Al-Karmalawy, Editor PONE-D-24-38269R1Identification of Novel Cyclin-dependent kinase 4/6 Inhibitors from Marine Natural ProductsPLOS ONE Dear Dr. Debnath, 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 Dec 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 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, Ahmed A. Al-Karmalawy, PhD 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. 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: N/A Reviewer #2: I Don't Know ****** 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: (No Response) Reviewer #2: All of my comments have been addressed. My only suggestion would be uploading high quality plots with readable legends and axis titles. Some figures are fuzzy and labels are too small to be readable. ****** 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 Reviewer #2: 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.0313830.r003
Revision 2
31 Oct 2024 Author Response To The Editor PLOS ONE Subject: Response Letter and Revised Manuscript Submission Dear Sir, I thank the reviewers for reviewing our paper submitted to the esteemed journal "PLOS ONE". The reviewers' feedback has been greatly appreciated and we have diligently addressed each comment in our amended article. We have highlighted in yellow color all the text that has been added or changed in the revised manuscript. Here is our detailed reply, Reviewer # 1: (No Response) Reviewer # 2: Problem 1: All of my comments have been addressed. My only suggestion would be uploading high quality plots with readable legends and axis titles. Some figures are fuzzy and labels are too small to be readable. Reply 1: As per the suggestion of the reviewer, we have uploaed the high quality figures. Thanking you With regards Abhijit Debnath Asst. Professor Noida Institute of Engineering and Technology (Pharmacy Institute), India; Attachments Attachment Submitted filename: Response to Reviewers2.pdf https://doi.org/10.1371/journal.pone.0313830.r004
1 Nov 2024 Decision Letter - Ahmed A. Al-Karmalawy, Editor Identification of Novel Cyclin-dependent kinase 4/6 Inhibitors from Marine Natural Products PONE-D-24-38269R2 Dear Dr. Debnath, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Ahmed A. Al-Karmalawy, PhD Academic Editor PLOS ONE Reviewers' comments: https://doi.org/10.1371/journal.pone.0313830.r005
Formally Accepted
6 Jan 2025 Acceptance Letter - Ahmed A. Al-Karmalawy, Editor PONE-D-24-38269R2 PLOS ONE Dear Dr. Debnath, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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 Associate Professor Ahmed A. Al-Karmalawy Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0313830.r006

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