In Silico Analysis of Methylprednisolone Derivatives: DFT Studies and Molecular Docking Analysis Against Monkeypox Protein

Monkeypox is an emerging zoonotic disease caused by the monkeypox virus, a member of the Orthopoxvirus genus, characterized by symptoms, such as fever and lymphadenopathy, with distinctive skin rashes transmitted through direct contact with infected individuals or animals. Currently, there is no specific antiviral treatment approved for monkeypox; however, antiviral agents used for smallpox, such as tecovirimat and brincidofovir, have shown efficacy against monkeypox in laboratory studies. By analyzing recent outbreaks and response strategies, we aim to synthesize steroidal derivatives that may serve as potent therapeutic agents for this infectious disease. In the present research paper, we synthesized the methylprednisolone derivatives (1a-1d) with the help of Steglich esterification using a dehydrating agent N, Nꞌ-dicyclohexyldicarbodiimide (DCC) and N, Nꞌ- dimethyl-4-aminopyridine (DMAP) as a catalyst. The structures of all synthesized methylprednisolone derivatives were identified using advanced spectroscopic techniques, including 1H NMR, 3C NMR, IR, UV-Vis, and ESI-MS. Experimental values correlated with theoretical predictions through DFT/B3LYP calculations. Hydrogen bonding and various interactions were thoroughly analyzed using Bader’s 'Atoms in Molecules' (AIM) theory. The HOMO-LUMO energy gap indicated a high level of chemical reactivity for the compounds, with Compound 1a exhibiting nonlinear optical (NLO) behavior due to a high first hyperpolarizability value of 9.06 × 10–30 esu. Molecular docking studies of methylprednisolone derivatives 1a, 1b, 1c, and 1d against monkeypox protein (4QWO) revealed binding energies of -10.7 kcal/mol, -11.0 kcal/mol, -8.6 kcal/mol, and -9.3 kcal/mol, respectively. These results suggest that the methylprednisolone derivatives exhibit inhibitory activity against the monkeypox protein.