In Silico Identification of Potential Inhibitors for Dengue Virus NS5 Methyltransferase: Molecular Docking, Dynamics, DFT, and ADME Analysis

Abstract Dengue virus (DENV) is a major global health concern, infecting over 100 million people annually with high mortality due to the absence of effective antiviral therapies. The NS5‐methyltransferase (NS5‐MTase), crucial for DENV replication, is a promising target for drug development. This study investigated phytocompounds as potential NS5‐MTase inhibitors. A virtual screening of 25,000 phytocompounds against the S‐adenosylmethionine (SAM) binding site identified four promising inhibitors (CNP0014493, CNP0014756, CNP0018882, and CNP0019696) based on docking scores and binding interactions. Molecular dynamics (MD) simulations, confirmed the stablity of these inhibitor complexes under physiological conditions, with free energy landscape analysis further supporting their thermodynamic stability. Density functional theory (DFT) study revealed that CNP0019696 and the reference compound exhibited favorable electronic properties for strong binding interactions. Additionally, in silico ADME (absorption, distribution, metabolism, and excretion) analysis suggested favorable physicochemical properties, indicating good drug‐like characteristics and bioavailability. Among the candidates, CNP0014493 and CNP0014756 emerged as the most promising, demonstrating significant potential as therapeutic agents for dengue treatment. These findings underscore the importance of targeting NS5‐MTase in developing effective antiviral therapies and highlight the potential of phytocompounds in contributing to the global fight against DENG.