Unlocking the antiviral potential of chalcones: A computational approach against dengue virus NS5 Protein

Dengue virus (DENV), a Flaviviridae member, poses a global health challenge due to the absence of effective antiviral therapies. The viral nonstructural protein 5 (NS5), responsible for RNA synthesis and methylation, is a validated drug target. This study aimed to identify potential chalcone-based inhibitors of the NS5 methyltransferase domain.

Forty chalcone derivatives from PubChem database were docked against the NS5 methyltransferase domain (PDB ID: 6KR2). The top six compounds were evaluated for drug-likeness (SwissADME) and toxicity (ProTox-II). Electronic properties were assessed using Density Functional Theory (DFT).

Six chalcones showed better binding affinities (≥-7.0 kcal/mol) than the reference ligand S-adenosylhomo-cysteine (SAH, -6.2 kcal/mol), interacting effectively with the SAM-binding pocket. BL-1 had the strongest docking score (-7.8 kcal/mol) but showed toxicity concerns. BL-3 emerged as the most promising, with strong binding (-7.4 kcal/mol), excellent drug-likeness, low toxicity, and good synthetic accessibility. DFT analysis revealed that BL-4 had the lowest energy gap (ΔΕ=3.59 eV), indicating high reactivity, while BL-3 had a stable HOMO (-6.45 eV) and a moderate energy gap (ΔΕ=4.22 eV), suggesting a favorable balance of reactivity and stability.

BL-3 shows strong potential as an NS5 methyltransferase inhibitor due to its optimal binding, safety profile, and electronic properties. It is recommended for further lead optimization and experimental validation as a candidate anti-DENV agent.