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

Area of Science:

• Biochemistry and Molecular Biology
• Virology
• Drug Discovery and Development

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global health concern, necessitating novel antiviral treatments beyond vaccination.
• Masitinib (MST), a tyrosine kinase inhibitor, has demonstrated inhibitory activity against the SARS-CoV-2 main protease (Mpro), a critical viral enzyme.

Purpose of the Study:

• To conduct a comprehensive molecular dynamics simulation analysis of the interaction between masitinib (MST) and the SARS-CoV-2 main protease (Mpro).
• To investigate the influence of Mpro H163 residue protonation and MST titratable groups on complex stability.
• To identify specific MST substituents and Mpro mutations impacting the MST-Mpro complex stability for improved drug design.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze the crystal structure of the MST-Mpro complex.
• The study examined the effects of varying protonation states for key residues and drug titratable groups.
• Analysis focused on identifying structural features of both MST and Mpro that modulate binding stability.

Main Results:

• The study elucidated the dynamic behavior of the MST-Mpro complex through extensive molecular simulations.
• Specific protonation states of Mpro's H163 residue and MST's titratable groups were found to significantly affect complex stability.
• Key MST substituents and Mpro mutations influencing the stability of the drug-enzyme interaction were identified.

Conclusions:

• The findings provide crucial insights into the molecular mechanisms governing the interaction between masitinib and SARS-CoV-2 Mpro.
• This detailed analysis supports the rational design of novel masitinib analogs with enhanced efficacy for COVID-19 treatment.
• The study highlights the importance of considering protonation states and specific molecular modifications for optimizing antiviral drug development.