Phytochemical inhibitors against MPOXV: Insights from molecular dynamics simulation and pharmacokinetics profile

The zoonotic orthopoxvirus, monkeypox (MPOXV), has emerged as a significant public health concern. Repurposed smallpox antivirals are the foundation of current treatment efforts; nevertheless, these alternatives have limitations. Considering the broad-spectrum antiviral action and reduced toxicity, medicinal plants and their bioactive components have drawn interest as potential drug sources. Therefore, this study employs computer-aided drug design (CADD) approach to explore phytochemicals derived from Azadirachta indica , aiming to identify potential inhibitors of MPOXV. Subsequently, 418 phytochemicals were assessed for targeting monkeypox thymidylate kinase (MPOX_TMPK) through molecular docking and pharmacokinetic analyses. With docking scores below -7.0 kcal/mol, the 298061, 5281654, 5280343, 5280863, and 8468 showed notable binding affinities for the TMPK. The 5280343 had the strongest binding affinity (-9.2 kcal/mol), interacting robustly with key active site residues, including ARG-41, PHE-68, ARG-93, and TYR-144. Additionally, the bioactive compounds exhibited favorable drug-like properties as suggested by the pharmacokinetic profile. Further, molecular dynamics simulations validated the stability of these complexes, with the 5281654 demonstrating minimal conformational variations (RMSD: 0.14 nm) and maintaining compact structural integrity (Rg: 1.32 nm). The SASA analysis suggested that the 5280343 and 5280863 caused minimal conformational expansion upon binding. These results underscore the therapeutic potential of phytochemicals derived from A. indica against MPOX_TMPK, urging additional experimental validation and optimization for antiviral drugs targeting MPOXV. Additionally, in vivo experiments must be conducted to confirm these findings and advance therapeutic prospects against MPOXV.