Molecular dynamics-driven optimization of triterpenoid, amidinium, and flavonoid inhibitors targeting dengue NS2B-NS3 protease

Dengue virus remains one of the most significant worldwide threats and has yet to yield to effective antiviral therapies. The viral NS2B-NS3 protease is a critical factor for dengue virus infection and is a validated target of therapeutic interest. In this work, we present a computational drug-design and similarity-based prioritization approach to evaluate triterpenoid, amidinium, and flavonoid inhibitors with their structural analogues. We have examined the binding modes, conformational stability, and energetic profiles of the molecules through molecular docking and explicit-solvent molecular dynamics simulations. While parent compounds (Glycyrrhizin, Benzamidine, and Myricetin; abbreviated as GLY, BENZ, and MYR) exhibited moderate to strong binding affinities, their derivatives demonstrated expanded interaction networks and enhanced occupancy within the deeper hydrophobic pockets of the active site. Free-energy landscapes unveiled thermodynamically favourable states with compact minima in GLY- and MYR-based systems. In addition, principal component analysis revealed ligand-dependent modulation of catalytic-site dynamics. MM/PBSA calculations yielded more favourable binding energies for derivatives, especially GLY-D and BENZ-D, driven by non-bonded interactions results identify tractable scaffold families whose members enhance protease stabilization and frame a rational basis for prioritizing candidates toward experimental evaluation for dengue antiviral development. The present study thus offered a thorough framework for finding lead compounds for additional drug optimization and design as NS2B-NS3 protease inhibitors, as well as insightful information about the interactions between active derivatives and DENV NS2B-NS3 protease.