Computational Discovery of Novel Monkeypox Virus DNA Polymerase Inhibitors from the Zinc20 Database

Monkeypox virus (MPXV) is emerging as a global public health concern due to its nature of spread. There are limited treatment options, as the sole drug for treatment is lacking, highlighting the need for new therapeutic options. The use of computer-aided drugs discovery such as molecular docking, molecular dynamic (MD) simulations and post-simulation analysis are important tools in identifying potential compounds that can target specific proteins of the virus, such as DNA polymerase to stop virus replication. This study employed molecular docking and molecular simulation with the aim to identify potential inhibitors for MPXV treatment from the ZINC Database. Molecular docking was performed using PyRx 0.8 version after virtual screening of the ZINC database using the Tranches tool; then, toxicity prediction of the selected compounds was performed using the ProTox-3.0 web server. Molecular dynamics simulation was conducted using GROMACS version 4.5 to evaluate the structural stability and dynamic behavior of the protein–ligand complex for the best interacting compound. Furthermore, post-simulation analysis was conducted using standard GROMACS utilities for visualizing time-dependent properties from MD simulations. A total of 16 compounds were shortlisted based on their molecular docking scores and interaction profiles with the monkeypox virus DNA polymerase (PDB ID: 8HG1). The leading compound, ZINC000019418450, demonstrated strong binding affinity (−7.4 kcal/mol). According to post-simulation analysis, all top compounds formed between one and five hydrogen bonds and up to eleven hydrophobic contacts with residues within the active site, thus providing strong geometric and energetic evidence for binding stability. Notably, our identification of ZINC000104288636 as a Class 6 compound with an LD50 of 23,000 mg/kg adds translational value by highlighting candidates with low predicted acute toxicity. Overall, this study lays a solid foundation for the rational design of next-generation monkeypox antiviral therapeutics. Future work is needed for experimental validation of prioritized compounds to assess their biochemical efficacy and pharmacological potential.