Dear Dr. Kim,

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We look forward to receiving your revised manuscript.

Kind regards,

Lalit Samant

Academic Editor

PLOS One

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This study supported by Sunchon National University.

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This study supported by Sunchon National University.

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This study supported by Sunchon National University.

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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?

Reviewer #1: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: No

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The manuscript appears to be well written with few punctuation errors. The authors are requested to perform a grammar check. The authors are advised to use proper mathematical operators for multiplication symbol instead of letter x. With regards to the MD simulation, the runtime of 50ns is short and the authors are advised to redo the simulation for 100 ns to ensure the sability of the protein-ligand complex stabilization

Reviewer #2: Major Comments

1. The study relies entirely on in silico approaches without experimental validation of D2 receptor antagonistic activity or prolactin secretion, which limits the translational significance of the findings. Inclusion of at least preliminary in vitro validation would substantially strengthen the conclusions.

2. The manuscript does not adequately evaluate receptor selectivity against other monoamine receptors such as 5-HT2A, H1, or α1 adrenergic receptors, despite risperidone’s known promiscuity.

3. BBB impermeability was predicted solely using the BOILED-Egg model and SwissADME parameters. Additional computational approaches such as CNS MPO score, logBB prediction, or P-gp substrate analysis should be included to improve confidence in peripheral restriction.

4. Molecular dynamics simulations were limited to 50 ns, which may not sufficiently capture long-term conformational stability of GPCR–ligand complexes.

5. The manuscript highlights Compound #381 as the lead candidate, but no comparative discussion is provided regarding its synthetic feasibility, predicted toxicity, or metabolic stability relative to existing drugs like domperidone or risperidone.

6. The docking validation strategy is insufficiently described. Re-docking of risperidone with RMSD comparison to the crystal pose should be reported quantitatively to validate the docking protocol reliability.

7. The discussion overstates the neuroprotective therapeutic potential despite lacking biological evidence that peripheral prolactin elevation alone can reproduce CNS protection without direct central D2R effects. The conclusions should be moderated accordingly.

Minor Comments

1. Several grammatical inconsistencies and spacing errors are present throughout the manuscript, such as “intermediate[21]” and inconsistent formatting around citations. Careful language editing is recommended.

2. The numbering of residues using both model-based numbering and Ballesteros–Weinstein notation may confuse readers. A clearer explanatory table or schematic would improve readability.

3. The manuscript frequently repeats descriptions of Asp(3.32) and Trp(6.48) interactions across sections, which could be condensed to avoid redundancy.

4. Table 1 contains lengthy SMILES strings that reduce readability.

5. Figure legends are highly detailed and somewhat repetitive. Simplifying the legends while keeping essential methodological information would improve clarity.

6. The authors mention cardiotoxicity concerns related to hERG inhibition but do not provide any in silico hERG liability prediction for the shortlisted compounds. Including this information would strengthen the safety assessment.

7. The Data Availability statement appears incomplete because docking files, MD trajectories, and processed datasets are not explicitly deposited in a public repository.

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Reviewer #1: No

Reviewer #2: No

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

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Identification of novel peripherally restricted risperidone-like dopamine D2 receptor antagonists for prolactin-mediated neuroprotection through a multi-stage in silico screening

PONE-D-26-16779R1

Dear Dr. Kim,

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.

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Kind regards,

Lalit Samant

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: