Computational and Experimental Exploration of Statin and Statin-like Compounds as Potential Treatment of Schistosomiasis.

PLOS Neglected Tropical Diseases

Dear Dr. PAUL-ODENIRAN,

Thank you for submitting your manuscript to PLOS Neglected Tropical Diseases. After careful consideration, we feel that it has merit but does not fully meet PLOS Neglected Tropical Diseases'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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We look forward to receiving your revised manuscript.

Kind regards,

David J. Diemert, M.D.

Academic Editor

PLOS Neglected Tropical Diseases

Jong-Yil Chai

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

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2) We have noticed that you have uploaded Supporting Information files, but you have not included a list of legends. Please add a full list of legends for your Supporting Information files after the references list.

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1) State what role the funders took in the study. If the funders had no role in your study, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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Reviewers' Comments:

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: The objective of the study was to use a computational pipeline to systematically identify and optimize SmHMGR inhibitors. The computational part of the study, although extensive, lacks objectivity and it is reflected on the modest antischistosomal activities found for the final compounds selected by the computational pipeline. The computational methodology is based on structure-based drug design tools but the experimental validation is performed by phenotypic assays. This causes an important gap between the computational predictions and computational results. Authors didn't discuss this important aspect of their study. Are such modest experimental findings the result of poor performance of the computational methodology or the inherent hurdles in translating target-based predictions to in vitro biological activities on whole organisms?

Other specific points for consideration:

- Authors should define “activity” early on the manuscript. It seems form pieces of information scattered across the manuscript that “activity” is the percentage of dead parasites. In this case, authors should clearly define how parasite death was assessed.

- Topic 2.1: What changes from each of the 140 models to the other?

- Topic 2.2: Is atorvastatin a known ligand of SmHMGR. What makes it a good template to search for other inhibitors of the enzyme?

- Line 128: “atorvastatin and each SmHMGR model were optimally formatted in .pdb files”. What exactly this means? What were the preparation steps?

- Lines 197-198: Please clarify. What do the authors mean by "stereochemical variability"? How 10 stereoisomers can be generated per ligand?

- Lines 203-204: Specify what algorithm was used with what restraints, number of minimization steps and convergence criteria.

Reviewer #2: Minor questions and comments to be addressed by authors in the attached file.

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: Topic 3.2 (Inverse docking): Are there any published methodological papers supporting this claim? I'm not convinced of the utility of this approach. The major flaw for me is that you are using a docking protocol, which has not been validated to select target models.

Minor issues:

- Line 353 and 390: Define "strong". Please use RMSD metric. Define "robust" and "stable", authors should try to be as objective as possible using quantitative strucutral parameters to support their observations instead of vague adjectives.

- Fig 1: The last G (human) and D (SCHMA) are highlighted but are distinct. There is also a V-L pair between 240 and 300

-Line 403: What is rec061?

Reviewer #2: Minor questions and comments to be addressed by authors in the attached file.

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: The conclusions are, for the most part, not supported by the data. For instance, authors state in line 774 that "analogues of pitavastatin (Table 9) exhibited promising activity". Based on what premises? What is the target activity/potency profile for an initial hit in schistosomiasis drug discovery?

Authors also claim to have "optimized" statin analogues but optimization is the process where one start from an initial hit and then optimize the chemical structure to improve biological activities. But activity of the parent compound was not known.

Reviewer #2: Minor questions and comments to be addressed by authors in the attached file.

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Overall, authors use a large part of the manuscript to describe computational results that ended up not performing as well as expected in terms of experimental validation. The manuscript would gain a lot in readability if the authors made an effort to only described the most relevant results and the ones directly relating to the experimental results. Everything else should be move to supplementary material.

Reviewer #2: Minor questions and comments to be addressed by authors in the attached file.

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: In Summary, this study aimed to employ structure-based drug design computational tools to identify new inhibitors of SmHMGR, a rising target for antischistosomal drug discovery. The study is greatly limited by the fact that experimental validation of the results are obtained straight from phenotipc assays on in vitro cultivated parasites without first testing on the molecular target. Althogh this approach is feasible, authors seem to completely ignore it in their discussion and make overstatements about the performance of the computational approach. In my view there is interesting data woth publishing in this manuscript but should be majorly reorganized to become more concise and focused on the discussion of the experimental results in view of the limitations of the computational approach.

Minor issues:

Introduction:

Line 65: authors should more accurately discuss this PZQ limitations since the latter is actually able to kill schistosomula in vitro at least and consider the juvenile stage as well.

Lines 80-81: Discuss similarity with human homologue and discuss potential selectivity issues.

Line 85: How many statins have been found to actually inhibit SmHMGR? A figure identifying the most potent ones would be relevant in the introduction.

Reviewer #2: Minor questions and comments to be addressed by authors in the attached file.

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Reviewer #1: No

Reviewer #2: No

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Reproducibility:

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Attachments

Attachment

Submitted filename: Reviewer comments_PNTD.pdf

Dear Dr PAUL-ODENIRAN,

We are pleased to inform you that your manuscript 'Computational and Experimental Exploration of Statin and Statin-like Compounds as Potential Treatment of Schistosomiasis.' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

David J. Diemert, M.D.

Academic Editor

PLOS Neglected Tropical Diseases

Jong-Yil Chai

Section Editor

PLOS Neglected Tropical Diseases

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-4304-636XX

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

orcid.org/0000-0003-1765-0002

***********************************************************

Reviewer #1:

Reviewer #2:

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: I'm satisfied with the changes and comments provided by the authors.

Reviewer #2: (No Response)

**********

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