In silico investigation and identification of potential phytocompounds targeting dengue virus NS5 methyltransferase

Dengue is an escalating public health threat in warm climate zones, particularly in tropical and subtropical regions. The World Health Organization (WHO) recorded approximately 4 million cases and 3000 deaths in 97 countries between January and July 2025, highlighting the urgent need for effective antiviral therapeutics. The presence of four genetically distinct serotypes of dengue virus (DENV) and the lack of a broadly effective drug pose major challenges for disease control. This study utilized an in silico approach to suggest potential phytocompounds targeting the non-structural protein 5 (NS5) methyltransferase, a crucial protein involved in 5'-mRNA capping. A total of 605 phytocompounds from Allium sativum, Curcuma longa, Camellia sinensis, and Carica papaya were screened based on Lipinski's rule of five and docked against the NS5 methyltransferase protein. Eight compounds exhibited higher predicted binding affinities than the control (-7.648 kcal/mol) with Dehydrocarpaine-I showing the most favorable predicted binding affinities (-9.456 kcal/mol). Top candidates were further evaluated based on their pharmacokinetic properties, toxicity profiles, and the protein-ligand interactions. Molecular dynamics simulations and principal component analysis (PCA) suggested the stability and favorable dynamic behavior of Dehydrocarpaine-I, Theasapogenol-B, and Brassinolide. MM-PBSA calculations showed that Theasapogenol-B (-62.48 kcal/mol) and Brassinolide (-44.82 kcal/mol) exhibited more favorable binding free energies compared to the control (-43.46 kcal/mol). This study suggests Theasapogenol-B and Brassinolide as potential lead compounds targeting NS5 methyltransferase and provides a basis for further comprehensive in silico, in vitro and in vivo validation.

The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00723-3.