PONE-D-21-11598

Dabrafenib Acts as a Significant Allosteric Modulator for Dengue NS3 Protease

PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The authors present a thorough in situ modeling approach to predict potential of small peptides to competitively bind to Dengue NS3 non-active site (allosterically) using routine molecular modeling tools. The authors identify 3 lead small molecules based upon their delta KCal/mol values of binding (< -9 kcal/mol): Dabrafenib, idelalisib and nintedanib.

As there is no current approved therapy or antiviral (small molecule) for Dengue, a positive control was not available. However, authors referenced in conclusions previous studies with prochlorperazine (PCZ) which also had in vitro data supporting possible antiviral activity for Dengue (targeting NS3 protease). Why was PCZ not included in initial screening as control to validate modeling assays to others in the field? Notably, in Table 2, suggest include PCZ for comparison to 3 "hit" compounds.

Secondly, why do authors focus on Dabrafenib (title) when appears 3 hits were identified. Also, could be argued that based upon FIg 5, Idelalisib is predicted to have most impact on altering structure of NS3 protease (via allosteric binding). Caution that focus on Dabrafenib suggests conflict of interest or personal interests.

Third, suggest grammar/text be reviewed by expert editor as several spacing, capitalization, spacing and subscript use is inconsistent. Most notably, Fig 6 has mislabel of top figure (labeled twice as idelalisib, suggest it should be "dabrafenib".).

Lastly, as this is only predictive, clearly in vitro work is necessary follow up and more relevant going forward to confirm antiviral potential and more importantly to determine potential toxicity. As these are anticancer drugs, toxicity is often associated. targeting protease is likely to have non-specific interaction with host proteases as well. Must test for potential tox.

Reviewer #2: the authors try to established three drug molecules (dabrafenib, idelalisib and nintedanib)against all the dengue serotypes (dengue1, dengue 2, dengue 3, dengue 4 & dengue 4T) protease. All the three drugs candidates show stable and strong binding with dengue NS3 based on the authors analysis. The author has done sufficient in silico study to investigate potentially of three drugs inhibiting dengue virus through dengue protease (NS3/NS2B). I have no objection to proceed this manuscript for publishing.

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Reviewer #1: No

Reviewer #2: Yes: Pouya Hassandarvish

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Dabrafenib, Idelalisib and Nintedanib Act as Significant Allosteric Modulator for Dengue NS3 Protease

PONE-D-21-11598R1

Dear Dr. Maiti,

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,

Keivan Zandi

Academic Editor

PLOS ONE

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