-->PONE-D-24-49878-->-->Identifying novel inhibitors against drug-resistant mutant CYP-51 Candida albicans: A computational study to combat fungal infections-->-->PLOS ONE

Dear Dr. Ali,

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.

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Please include the following items when submitting your revised manuscript:-->

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We look forward to receiving your revised manuscript.

Kind regards,

Ahmed A. Al-Karmalawy, PhD

Academic Editor

PLOS ONE

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When submitting your revision, we need you to address these additional requirements.

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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

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: N/A

Reviewer #2: Yes

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-->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

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-->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

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-->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: Is the manuscript technically sound, and do the data support the conclusions?

Partly

Has the statistical analysis been performed appropriately and rigorously?

N/A

Have the authors made all data underlying the findings in their manuscript fully available?

Yes

Is the manuscript presented in an intelligible fashion and written in standard English?

Yes

1.Avoid abbreviations in the abstract.

2.Avoid abbreviations in keywords.

3.Please indicate the full name of each abbreviation when it first appears in the draft.

4.Enhance the introduction section of your study by incorporating the specified articles to compare your results with those of other studies.

5.2D structures in Table One should all be in the same size and style.

6.The titles of all figures should be written more scientifically.

7.Use more recent references.

Reviewer #2: The authors of the provided manuscript evaluated the anti-Candida albicans activity of PubChem deposited compounds against the drug-resistant mutant CYP-51 through computational approaches. This manuscript is relevant to the field of drug discovery. Few points are to be addressed prior publication.

1. Authors should elaborate more, providing more details on the target topology and pocket description prior presenting the docking findings.

2. Positive control reference compound should be adopted throughout the study to provide significance for the obtained computational findings in terms of relevant biological translation.

3. Authors should elaborate more on the ligand-target interaction patterns Bonding should be annotated in terms of both the bond distances and angles. Specially for Hydrogen bonding, this type of compound-protein polar interaction should be presented within hydrogen bond distances as well as bond angles since hydrogen bond depend on both. Authors should mention the Hydrogen bond angles as well as their distances, since the strength of hydrogen bonding is based on both parameters in a way to ensure the adequacy of optimum hydrogen bonding.

4. The author provided dissection of the free binding energies calculations estimated from the MD simulation trajectories in terms of ∆G electrostatic, ∆G van der Waal, ∆G polar solvation, ∆G non-polar SASA solvation,…) to identify the dominant energy terms that can guide further ligand optimization and development.

Further, the total free binding energies for compound-target complex should be broken down to the target residue energy contribution to highlight which residues impose the great impact on ligand binding for future targeting and lead optimization

5. Authors are advised to provide snap shoot of the MD simulated ligand-protein complex at different time intervals (example 0ns, 50ns, 100ns, 150ns, and/or 200ns) to track the main conformational/orientation changes for both the compound and surrounding residues over time.

6. Based on the study results, what are the take-away messages. Authors are advised to highlight the suggested structural modifications that would improve the compound’s biological activities based on the in silico findings. These insights would be beneficial for guiding further lead optimization and development.

7. Finally, concerning the conclusion, authors are advised to elaborate more on the future of this work? Will you broaden the scope to another drug target? What are the study limitations and what approaches could be conducted to further address them?

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-->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: Yes

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[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.

Identifying novel inhibitors against drug-resistant mutant CYP-51 Candida albicans: A computational study to combat fungal infections

PONE-D-24-49878R1

Dear Dr. Ali,

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:

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: (No Response)

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-->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: (No Response)

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-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: N/A

Reviewer #2: (No Response)

**********

-->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: (No Response)

**********

-->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: (No Response)

**********

-->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 the comments have been addressed

Is the manuscript technically sound, and do the data support the conclusions

yes

Has the statistical analysis been performed appropriately and rigorously?

N/A

Have the authors made all data underlying the findings in their manuscript fully available?

yes

Is the manuscript presented in an intelligible fashion and written in standard English?

yes

Reviewer #2: (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

Reviewer #2: Yes

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