Discovery of Novel SARS-CoV-2 Main Protease Inhibitors Through Integrated Docking, ADMET, DFT, and Normal Mode Analysis

The SARS-CoV-2 main protease (Mᵖʳᵒ) plays a crucial role in viral replication and is a key target for antiviral drug development. This study aimed to evaluate phytochemical inhibitors of Mᵖʳᵒ, focusing on their binding affinity, stability, pharmacokinetics, and toxicity. After the ligand screening, 5 major phytochemicals, Tanshinone IIA, Tanshinone IIB, Isocryptotanshinone, Tanshindiol C and Oleanolic acid were chosen to be investigated further. Computational methods were used to determine their molecular stability, quantum chemical properties, binding affinities, pharmacokinetic profiles and toxicity. The pharmacokinetic profiling showed that it had high gastrointestinal absorption, moderate water solubility, blood–brain barrier permeability, and good metabolic properties. ProTox-II and StopTox toxicity prediction revealed that Tanshinone IIA is not toxic in acute oral, dermal and inhalation studies and has low chances of organ toxicity, mutagenicity or carcinogenicity. Analysis of molecular docking indicated that Tanshinone IIA (−7.5 kcal/mol) was strongly bound to key catalytic sites of Mᵖʳᵒ, such as HIS41, CYS145, GLU166, THR25, THR26 and LEU27 with the help of hydrogen bonds and hydrophobic forces. The optimization of the density functional theory (DFT) ensured that the molecular conformations were stable and Tanshinone IIA was found to have lower energy after optimization. Normal Mode Analysis also indicated that there was a stable and flexible Tanshinone IIA–Mᵖʳᵒ complex with low energy of conformational transitions. All in all, these results demonstrate that Tanshinone IIA is an excellent lead compound with high inhibitory potential, good pharmacokinetic characteristics, and low toxicity, which can be further experimentally proven as a therapeutic agent against SARS-CoV-2.