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Drug repurposing against the RNA-dependent RNA polymerase domain of dengue serotype 3 by virtual screening and molecular dynamics simulations.
J Biomol Struct Dyn. 2023 07; 41(11):5152-5165.JB

Abstract

Dengue is an arboviral disease caused by the dengue flavivirus. The NS5 protein of flaviviruses is a potential therapeutic target, and comprises an RNA-dependent RNA polymerase (RDRP) domain that catalyses viral replication. The aim of this study was to repurpose FDA-approved drugs against the RDRP domain of dengue virus serotype 3 (DENV3) using structure-based virtual screening and molecular dynamics (MD) simulations. The FDA-approved drugs were screened against the RDRP domain of DENV3 using a two-step docking-based screening approach with Glide SP and Glide XP. For comparison, four reported DENV3 RDRP inhibitors were docked as standards. The hitlist was screened based on the docking score of the inhibitor with the lowest docking score (PubChem ID: 118797902; reported IC50 value: 0.34 µM). Five hits with docking scores and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) energy lower than those of 118797902 were selected. The stability of the hit-receptor complexes was investigated using 100 ns MD simulations in an explicit solvent. The results of MD simulations demonstrated that polydatin and betiatide remained stably bound to the receptor, and formed stable interactions with the RDRP domain of DENV3. The hit-receptor interactions were comparable to those of 118797902. The average Prime MM-GBSA energy of polydatin and betiatide was lower than that of 118797902 during simulation, indicating that their binding affinity to DENV3 RDRP was higher than that of the standard. The results of this study may aid in the development of serotype-selective drugs against dengue in the future.Communicated by Ramaswamy H. Sarma.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Gangopadhyay A
Department of Chemical Technology, University of Calcutta, Kolkata, India.
Saha A
Department of Chemical Technology, University of Calcutta, Kolkata, India.

MeSH

HumansMolecular Dynamics SimulationRNA-Dependent RNA PolymeraseSerogroupDrug RepositioningDengueMolecular Docking Simulation

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35642087

Citation

Gangopadhyay, Aditi, and Achintya Saha. "Drug Repurposing Against the RNA-dependent RNA Polymerase Domain of Dengue Serotype 3 By Virtual Screening and Molecular Dynamics Simulations." Journal of Biomolecular Structure & Dynamics, vol. 41, no. 11, 2023, pp. 5152-5165.
Gangopadhyay A, Saha A. Drug repurposing against the RNA-dependent RNA polymerase domain of dengue serotype 3 by virtual screening and molecular dynamics simulations. J Biomol Struct Dyn. 2023;41(11):5152-5165.
Gangopadhyay, A., & Saha, A. (2023). Drug repurposing against the RNA-dependent RNA polymerase domain of dengue serotype 3 by virtual screening and molecular dynamics simulations. Journal of Biomolecular Structure & Dynamics, 41(11), 5152-5165. https://doi.org/10.1080/07391102.2022.2080764
Gangopadhyay A, Saha A. Drug Repurposing Against the RNA-dependent RNA Polymerase Domain of Dengue Serotype 3 By Virtual Screening and Molecular Dynamics Simulations. J Biomol Struct Dyn. 2023;41(11):5152-5165. PubMed PMID: 35642087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug repurposing against the RNA-dependent RNA polymerase domain of dengue serotype 3 by virtual screening and molecular dynamics simulations. AU - Gangopadhyay,Aditi, AU - Saha,Achintya, Y1 - 2022/05/31/ PY - 2023/6/14/medline PY - 2022/6/2/pubmed PY - 2022/6/1/entrez KW - Dengue KW - drug repurposing KW - molecular docking KW - molecular dynamics simulations KW - neglected tropical disease KW - virtual screening SP - 5152 EP - 5165 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 41 IS - 11 N2 - Dengue is an arboviral disease caused by the dengue flavivirus. The NS5 protein of flaviviruses is a potential therapeutic target, and comprises an RNA-dependent RNA polymerase (RDRP) domain that catalyses viral replication. The aim of this study was to repurpose FDA-approved drugs against the RDRP domain of dengue virus serotype 3 (DENV3) using structure-based virtual screening and molecular dynamics (MD) simulations. The FDA-approved drugs were screened against the RDRP domain of DENV3 using a two-step docking-based screening approach with Glide SP and Glide XP. For comparison, four reported DENV3 RDRP inhibitors were docked as standards. The hitlist was screened based on the docking score of the inhibitor with the lowest docking score (PubChem ID: 118797902; reported IC50 value: 0.34 µM). Five hits with docking scores and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) energy lower than those of 118797902 were selected. The stability of the hit-receptor complexes was investigated using 100 ns MD simulations in an explicit solvent. The results of MD simulations demonstrated that polydatin and betiatide remained stably bound to the receptor, and formed stable interactions with the RDRP domain of DENV3. The hit-receptor interactions were comparable to those of 118797902. The average Prime MM-GBSA energy of polydatin and betiatide was lower than that of 118797902 during simulation, indicating that their binding affinity to DENV3 RDRP was higher than that of the standard. The results of this study may aid in the development of serotype-selective drugs against dengue in the future.Communicated by Ramaswamy H. Sarma. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/35642087/Drug_repurposing_against_the_RNA_dependent_RNA_polymerase_domain_of_dengue_serotype_3_by_virtual_screening_and_molecular_dynamics_simulations_ DB - PRIME DP - Unbound Medicine ER -

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