Novel fungal metabolites as dual cholinesterase inhibitors: A computational approach for Alzheimer’s disease therapy

Md. Habib Ullah Masum; Syed Mohammad Lokman; Rehana Parvin; Md Shahidur Rahman; Erfanul Haq Chowdhury; Kazi Chamonara; Salma Chowdhury; Ahmad Abdullah Mahdeen; Mst. Mitu Khatun

doi:10.1371/journal.pone.0326219

Peer Review History

Original SubmissionMarch 29, 2025
29 Mar 2025 Author Response https://doi.org/10.1371/journal.pone.0326219.r001
Decision Letter - Noor Jahan, Editor PONE-D-25-16513Novel Fungal Metabolites as Dual Cholinesterase Inhibitors: A Computational Approach for Alzheimer's Disease TherapyPLOS ONE Dear Dr. Masum, 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: The manuscript is reviewed and according to remarks after minor revision the manuscript can be accepted for publication in PLOS ONE. Proteins codes must be referenced form recent research articles. One of the query of reviewer is why standards were not used for docking and simulation which might help in co-relation? if possible add standards. ============================== Please submit your revised manuscript by Jun 22 2025 11:59PM. 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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.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.] 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: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? 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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: 1) Was the licensed version of pymol used for the study. 3) Proteins codes must be referenced form recent research articles. 3) Why standards were not used for docking and simulation which might help in co-relation? 4) In-vitro results could also aid valuable findings to the study and why these were not performed? Reviewer #2: The article is well written and justifying the title and objectives. The Author used all necessary tools/softwares and parameters to explore the inhibitory potential of fungal metabolites on AChE and BuChE by CADD for the better treatment of Alzheimer Disease. The pictures, tables and figures are well justified. ****** 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.0326219.r002
Revision 1
16 May 2025 Author Response ACADEMIC EDITOR: The manuscript is reviewed and according to remarks after minor revision the manuscript can be accepted for publication in PLOS ONE. • Proteins codes must be referenced form recent research articles. Authors’ response: In accordance with your suggestions, we have incorporated recent research articles as references for the receptor proteins. The corresponding changes have been highlighted in yellow color. • One of the query of reviewer is why standards were not used for docking and simulation which might help in co-relation? if possible add standards. Authors’ response: We performed molecular docking studies between the receptor proteins and the control or standard drugs. However, for the molecular dynamics simulations, we used the apo structures of the receptor proteins as the standard, as it is a common practice to evaluate apo structures in comparison to their ligand-bound complexes in such studies. Studying the apo structure in molecular dynamics (MD) simulations is essential for understanding the intrinsic dynamics, flexibility, and stability of a protein in its unbound state. It serves as a baseline to compare with ligand-bound (holo) forms, helping to reveal conformational changes induced by ligand binding. Apo simulations can uncover transient or cryptic binding pockets that may not be visible in static crystal structures, which is valuable for drug discovery. Additionally, they provide insights into the structural integrity of the protein when not bound to a ligand and help elucidate potential allosteric mechanisms or conformational ensembles involved in its function. Reviewer #1: 1) Was the licensed version of pymol used for the study. Authors’ response: Many thanks for your contribution and critical observations on this paper. We believe, we have benefited much after going through this revision, and the manuscript’s quality has improved tremendously. Yes, we have used licensed version of pymol softaware. 2) Proteins codes must be referenced form recent research articles. Authors’ response: In accordance with your suggestions, we have incorporated recent research articles as references for the receptor proteins. The corresponding changes have been highlighted in yellow color. 3) Why standards were not used for docking and simulation which might help in co-relation? Authors’ response: We performed molecular docking studies between the receptor proteins and the control or standard drugs. However, for the molecular dynamics simulations, we used the apo structures of the receptor proteins as the standard, as it is a common practice to evaluate apo structures in comparison to their ligand-bound complexes in such studies. Studying the apo structure in molecular dynamics (MD) simulations is essential for understanding the intrinsic dynamics, flexibility, and stability of a protein in its unbound state. It serves as a baseline to compare with ligand-bound (holo) forms, helping to reveal conformational changes induced by ligand binding. Apo simulations can uncover transient or cryptic binding pockets that may not be visible in static crystal structures, which is valuable for drug discovery. Additionally, they provide insights into the structural integrity of the protein when not bound to a ligand and help elucidate potential allosteric mechanisms or conformational ensembles involved in its function. The references are provided below References: 1. Ibrahim, M.A.A., Abdeljawaad, K.A.A., Roshdy, E. et al. In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents. Sci Rep 13, 2146 (2023). https://doi.org/10.1038/s41598-023-28226-7 2. Akash, S., Bayıl, I., Hossain, M.S. et al. Novel computational and drug design strategies for inhibition of human papillomavirus-associated cervical cancer and DNA polymerase theta receptor by Apigenin derivatives. Sci Rep 13, 16565 (2023). https://doi.org/10.1038/s41598-023-43175-x 3. El Hassab, M.A., Eldehna, W.M., Hassan, G.S. et al. Multi-stage structure-based virtual screening approach combining 3D pharmacophore, docking and molecular dynamic simulation towards the identification of potential selective PARP-1 inhibitors. BMC Chemistry 19, 30 (2025). https://doi.org/10.1186/s13065-025-01389-2 4) In-vitro results could also aid valuable findings to the study and why these were not performed? Authors’ response: In-vitro experiments could undoubtedly contribute valuable mechanistic insights and serve to further substantiate the findings of this study. However, due to constraints related to resources, funds and the study’s primary focus on in-vivo or field-based outcomes, such experiments were not included in the current study. Nonetheless, we acknowledge the importance of in-vitro validation and consider it a logical next step in our future research to strengthen and expand upon the current findings. Reviewer #2: The article is well written and justifying the title and objectives. The Author used all necessary tools/softwares and parameters to explore the inhibitory potential of fungal metabolites on AChE and BuChE by CADD for the better treatment of Alzheimer Disease. The pictures, tables and figures are well justified. Authors’ response: Many thanks for your contribution and critical observations on this paper. We believe, we have benefited much after going through this revision, and the manuscript’s quality has improved tremendously. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0326219.r003
Decision Letter - Noor Jahan, Editor Novel Fungal Metabolites as Dual Cholinesterase Inhibitors: A Computational Approach for Alzheimer's Disease Therapy PONE-D-25-16513R1 Dear Dr. Masum, 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, Noor Jahan Academic Editor PLOS ONE Additional Editor Comments (optional): As the necessary revisions are made so manuscript should proceed for publication. Reviewers' comments: https://doi.org/10.1371/journal.pone.0326219.r004
Formally Accepted
Acceptance Letter - Noor Jahan, Editor PONE-D-25-16513R1 PLOS ONE Dear Dr. Masum, 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 You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days 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 Prof. Dr. Noor Jahan Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0326219.r005

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