In Silico Characterization of Masitinib Interaction with SARS‐CoV‐2 Main Protease

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection continues to be a global health problem. Despite the current implementation of COVID‐19 vaccination schedules, identifying effective antiviral drug treatments for this disease continues to be a priority. A recent study showed that masitinib (MST), a tyrosine kinase inhibitor, blocks the proteolytic activity of SARS‐CoV‐2 main protease (Mpro). Although MST is a potential candidate for COVID‐19 treatment, a comprehensive analysis of its interaction with Mpro has not been done. In this work, we performed molecular dynamics simulations of the MST‐Mpro complex crystal structure. The effect of the protonation states of Mpro H163 residue and MST titratable groups were studied. Furthermore, we identified the MST substituents and Mpro mutations that affect the stability of the complex. Our results provide valuable insights into the design of new MST analogs as potential treatments for COVID‐19. We performed molecular dynamics simulations to characterize the dynamic behavior of masitinib within the SARS‐CoV‐2 main protease (Mpro) active site. We identified three key interactions involved in complex stability that are altered by the high mobility of the methylpiperazine group. Overall, our results provide essential insights for the design of novel masitinib analogs as potential COVID‐19 drug treatments.