Integrative Computational Approaches for the Discovery of Novel Natural Carbazole Alkaloid Derivatives as Monkeypox Virus Inhibitors

The monkeypox virus (MPXV) has recently faced a global health concern, and it is urgent to discover potential antiviral agents. Carbazole alkaloids, known for their diverse pharmacological activities, have shown promise as antiviral candidates. In this study, we employ a computational approach to explore the inhibitory potential of natural carbazole alkaloid derivatives against key MPXV viral protein, using molecular docking, molecular dynamics (MD) simulation and ADMET profiling. This study involved 156 carbazole alkaloid derivatives. Among them compound 47 showed the best XP docking score −6.017 kcal/mol with the amino acid interactions TYR204, ALA206, ARG177, ARG140 (PDB: 8OIV). We also performed [Formula: see text]-group enumeration and the virtual screening of the enumerated compounds gave the top-scoring compounds S1, S2 and S3, with S1 exhibiting XP docking score −9.249 kcal/mol and the key amino acid interactions are TYR204, SER205, PHE180, ARG177, and ARG140. The crystal ligand of protein and the drug brincidofovir were used as the reference compounds with XP docking score −12.79 kcal/mol and −4.025 kcal/mol and the key interaction amino acids are LYS41, LYS175, ALA206, ARG177, SER205, TYR204, TYR22, PHE180, ASP182, LYS142, ARG140, ARG97. The MD simulation study indicated that S3 had the most stable interactions with ARG177 and ARG140, the amino acids responsible for substrate recognition and positioning of the G1 ribose for methylation. The ADMET tool gave the data on the physiochemical properties of the compounds. The findings of this investigation may aid in the future development of natural alkaloid derivatives that target the MPXV virus.