Structure-Based Discovery of Coumarin-Triazole Derivatives Targeting the Conserved QGDNQ Motif of Chandipura RdRp.

Abstract

Chandipura virus (CHPV) is a recently discovered neurotropic virus associated with severe encephalitis in children and for which there is currently no specific antiviral treatment. The viral RNA-dependent RNA polymerase (RdRp) is an attractive antiviral target because of its essential role in viral RNA synthesis and the presence of conserved catalytic motifs required for polymerase function. In this study, a structure-based computational approach was employed to investigate coumarin-triazole derivatives as potential inhibitors targeting the conserved QGDNQ motif-containing region of CHPV RdRp. A homology model of CHPV RdRp was generated and structurally evaluated, followed by prediction of the ligand-binding pocket. A set of 80 coumarin-triazole derivatives was subjected to extra-precision (XP) molecular docking, and compounds 7a, 7b, and 7d were identified as potential candidates based on their docking scores and predicted binding free energies. Compound 7a showed a favorable docking score and interactions with the residues close to the catalytic motif, especially ASN705. The ADMET analysis also indicated favorable physicochemical and pharmacokinetic properties for the selected compounds. Molecular dynamics simulations were subsequently performed for 200 ns for both the protein-only system and the ligand-bound complexes to assess their structural stability and conformational behavior. RMSD and RMSF analysis revealed that Compound 7a exhibited comparatively lower residue fluctuations among the ligand-bound systems. PCA indicated a more compact conformational distribution comparable to that observed for the remdesivir-bound system. Post-MD MM/GBSA analysis further supported the favorable binding of Compound 7a. Overall, the integrated computational analysis identified Compound 7a as a promising coumarin-triazole candidate for further investigation against CHPV RdRp. Experimental studies are required to validate its antiviral activity and mechanism, and the findings provide a basis for further optimization of the coumarin-triazole scaffold toward potential non-nucleoside CHPV RdRp inhibitors.

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