In Silico Discovery of SARS-CoV-2 Main Protease Inhibitors Using Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations
Takeshi Ishikawa, Kenji Matsumoto, Toshiyuki Hamada, Hinako Koze, Masanori Baba, Mika Okamoto, Masayuki Sudoh · The Journal of Physical Chemistry B · 2025
The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main protease (M pro ), is an attractive drug target for the treatment of coronavirus disease 2019. This study reports the discovery of novel M pro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, and 12 compounds were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant M pro inhibitory activity with an IC 50 of 11.1 μM. The identification of seed compounds from the experiments on a few compounds demonstrates the effectiveness of our docking calculations. Furthermore, the detailed analyses using MD and FMO calculations suggested an interaction mechanism in which the hydroxyl group of BP-1-102 forms a hydrogen bond with E166 of M pro . The M pro inhibitory activity of SH-4-54, a derivative without the aforementioned hydroxyl group, was investigated and observed to be significantly reduced, with an IC 50 of 81.5 μM. This result strongly supports the suggested interaction mechanism.