In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells

Chirasmita Nayak; Sanjeev Kumar Singh

doi:10.1371/journal.pone.0255803

Peer Review History

Original SubmissionJanuary 4, 2021
8 Feb 2021 Decision Letter - Jie Zheng, Editor PONE-D-21-00233 In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells PLOS ONE Dear Dr. Singh, 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 20 2021 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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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: This work screened some nature product inhibitors against Oct4 using virtual screening, docking, and MD simulation methods. Two compounds (ZINC02145000 and ZINC32124203) showed a stable and interaction with Oct4, indicating a potential inhibition ability of the two compounds against Oct4. But some issues should be addressed. (1) Figure 2 is hard to distinguish the interaction network of Oct4, the interaction map combining with a table would be a better to understand the interaction network of Oct4. (2) There almost no difference between modeled protein and the template protein from Figure 3d. The two figures are exactly same. (3) What is the accurate simulation time (50 ns in method section, 100 ns in result section)? From Figure 4a, the protein seems to haven’t reach to a equilibrium state, with great structural perturbation even from last 20 ns. (4) In Figure 4d and Figure 9 for second structure analysis, comparison of the ratio of the secondary structures between initial simulation time and equilibrium state is better to understand the structure transition of the protein. (5) In Figure 5, a close-up representation of specific binding residues of the Oct4 would be better to address the binding site. ****** 6. 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Revision 1
7 Jul 2021 Author Response Response to Decision Letter and Reviewer Comments We would like to thank the editors and reviewers for their constructive suggestions and comments to improve the quality and shape of our manuscript entitled “In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells”. We believe our refined manuscript is improved based on the reviewer suggestions. With this, we have addressed the each of their concerns as outlined below. Note: The reviewer’s comments are in black and italics. Author Responses are in red and bold text. Changes in the manuscript were highlighted within the manuscript (Ms) in red colour. Response to Reviewer #1: Comment 1: Figure 2 is hard to distinguish the interaction network of Oct4; the interaction map combining with a table would be a better to understand the interaction network of Oct4. We would like to thank the Reviewer for careful reading of this Ms and for the comment. As per the reviewer suggestion, the tabulated representation of interaction network of Oct4 has been added in the manuscript and highlighted in red color (Table 1). Comment 2: There almost no difference between modeled protein and the template protein from Figure 3d. The two figures are exactly same. We agree with the reviewer that our modeled protein structure is almost similar with template structure. There were only some differences in loop regions so they both superimposed perfectly with RMSD of 0.102Å which was indicating that the generated model is more reliable and accurate to perform further analysis. Comment 3: What is the accurate simulation time (50 ns in method section, 100 ns in result section)? From Figure 4a, the protein seems to have not reached to an equilibrium state, with great structural perturbation even from last 20 ns. We would like to thank reviewer for careful reading of this Ms. To address your query, we have performed 100ns molecular dynamics for apo protein while for complexes 50ns. We agree with reviewer. Since after 50ns, apo protein has not shown any stability during simulation then we have extended to 100ns time period. However after 100ns also the apo protein was exhibited high deviation and instability throughout the simulation then we try to find out the actual reason for the same through literature survey. We found an article publish in PLoS One (ref. No. 86) which has been discussed in the MS where they have reported that oct4 was highly unstable after insertion of only 3 base pairs in oct4 at oct4/sox2-DNA binding site which roughly packed protein arrangement and weaken the interactions between the Oct4 and Sox2 proteins. From this we have hypothesized that maybe oct4 will show stable conformation after binding with small molecule inhibitors. The hypothesis was confirmed by performing molecular dynamic simulation of complexes which disclosed that after binding with our screened compounds oct4 was stable even within 35ns. Hence we have not extended our dynamics to 100ns for complex proteins. Comment 4: In Figure 4d and Figure 9 for second structure analysis, comparison of the ratio of the secondary structures between initial simulation time and equilibrium state is better to understand the structure transition of the protein. As suggested by the reviewer, we have added one table stating the ratio of SSE of initial structure (apo protein) and compound binding proteins which has been highlighted in red color (Table 5). Comment 5: In Figure 5, a close-up representation of specific binding residues of the Oct4 would be better to address the binding site. As suggested by the reviewer, a closer representation of binding site with its amino acids has been induced in the figure 5 and incorporated in the manuscript. https://doi.org/10.1371/journal.pone.0255803.r002
26 Jul 2021 Decision Letter - Jie Zheng, Editor In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells PONE-D-21-00233R1 Dear Dr. Singh, 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, Jie Zheng, Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0255803.r003
Formally Accepted
3 Aug 2021 Acceptance Letter - Jie Zheng, Editor PONE-D-21-00233R1 In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells Dear Dr. Singh: 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. Jie Zheng Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0255803.r004

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