Computational Design of a Phytochemical Drug Candidate Targeting Monkeypox Virus D8l and D4r/A20r Complex: An in Silico Study of Pharmacophoreand Molecular Prediction

Abstract

Due to its rapid spread and the absence of approved antiviral treatments, Monkeypox virus (MPXV) has been declared as a global health emergency. This study aimed to identify possible drug candidates targeting MPXV vaccinia proteins D8L which is involved in host cell entry, and D4R/A20R Complex responsible for viral DNA replication and host cell entry. Phytochemical and pharmacophore compounds were assessed against MPXV target proteins using an in silico quantitative method that combined computational screening, molecular docking, and protein–ligand interaction analysis. Protein and ligand libraries were obtained from RCSB PDB, NCBI BLASTp, PubChem, and DrugBank. Drug-likeness and pharmacokinetic properties were assessed using ADMETLab 3.0. This screening reduced the initial number of 1,854 phytochemical and 808 pharmacophore compounds to 168 phytochemical and 11 pharmacophore candidates. The compounds that satisfied the former criterion were subjected to molecular docking and cavity assessment using CB-Dock which was then followed by an interaction analysis using PLIP. The leading ligands were then further evaluated using a criterion derived from docking rank, hydrogen bonds, and hydrophobic interactions gained. Among the three (3) methods, Artonol A and Camptothecin showed identical strong binding affinities of −9.1 kcal/mol and achieved the highest scores against their respective proteins. These findings support further experimental validation by in vitro and in vivo tests as possible choices for treating MPXV.