Identification of potential inhibitors of dengue virus ns5 methyltransferase and polymerase domains through virtual screening and molecular dynamics studies.

Authors

Nabeel Haider, Abolfazl Zare, Yi Zhou, Faez Iqbal Khan

Published in

Journal of molecular modeling. Volume 32. Issue 8. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

The dengue virus continues to pose a serious global health challenge due to the absence of effective antiviral therapies. Non-structural protein 5 (NS5), a multifunctional non-structural protein containing methyltransferase and RNA-dependent RNA polymerase domains, is essential for viral replication and represents a high-priority therapeutic target. In this study, potential inhibitors targeting two functional sites of Dengue virus serotype 3 (DENV-3) NS5 were identified through structure-based virtual screening and structural dynamics analysis. Docking results identified PubChem compound 135,625,223 as the strongest binder at the RNA-binding site with a binding affinity of - 11.8 kcal/mol, forming a hydrogen bond with Arg₄₈₁ and a hydrophobic interaction with Phe₄₈₅. Molecular dynamics simulations showed that the S-adenosylmethionine (SAM)-binding site ligand formed a more stable complex with lower root-mean-square deviation (RMSD) (0.26 nm) and reduced flexibility, indicating a promising lead candidate for further optimization and experimental validation against dengue virus NS5.
The full-length NS5 structure was constructed using homology modeling with MODELLER, ab initio modeling, and AlphaFold, and the best model was selected based on low RMSD and stereochemical quality. A library of 587 antiviral compounds retrieved from PubChem was docked against the SAM-binding site of the methyltransferase domain and the RNA-binding site of the polymerase domain using AutoDock Vina. The top-ranked ligands were further evaluated through Insilico screening and 300-ns molecular dynamics simulations using GROMACS.

PMID:
42418067
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.

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