Development of Masitinib Derivatives with Enhanced Mpro Ligand Efficiency and Reduced Cytotoxicity

by Selleckchem | Nov 20 2023

Recently, a high-throughput screen of 1900 clinically used drugs identified masitinib, an orally bioavailable tyrosine kinase inhibitor, as a potential treatment for COVID-19. Masitinib acts as a broad-spectrum inhibitor for human coronaviruses, including SARS-CoV-2 and several of its variants. In this work, we rely on atomistic molecular dynamics simulations with advanced sampling methods to develop a deeper understanding of masitinib's mechanism of Mpro inhibition. To improve the inhibitory efficiency and to increase the ligand selectivity for the viral target, we determined the minimal portion of the molecule (fragment) that is responsible for most of the interactions that arise within the masitinib-Mpro complex. We found that masitinib forms highly stable and specific H-bond interactions with Mpro through its pyridine and aminothiazole rings. Importantly, the interaction with His163 is a key anchoring point of the inhibitor, and its perturbation leads to ligand unbinding within nanoseconds. Based on these observations, a small library of rationally designed masitinib derivatives (M1-M5) was proposed. Our results show increased inhibitory efficiency and highly reduced cytotoxicity for the M3 and M4 derivatives compared to masitinib.

Comments:

It appears you're describing a scientific study focused on identifying masitinib and its derivatives as potential treatments for COVID-19. The study uses advanced techniques like molecular dynamics simulations to understand how masitinib inhibits the Mpro enzyme, a crucial component for the replication of SARS-CoV-2.

In summary, the key findings of this research are:

1. **Identification of Masitinib:** A high-throughput screening of drugs led to the identification of masitinib as a potential inhibitor for COVID-19. It was found to be effective against various human coronaviruses, including SARS-CoV-2 and its variants.

2. **Molecular Interaction:** Through molecular dynamics simulations, it was determined that masitinib forms stable hydrogen bond interactions with the Mpro enzyme. The specific interaction with a residue called His163 was identified as crucial; disruption of this interaction caused the inhibitor to unbind rapidly.

3. **Derivatives Design:** Using this understanding, the researchers designed several derivatives of masitinib (M1-M5) with the aim of improving its inhibitory efficiency and reducing cytotoxicity.

4. **Effective Derivatives:** Among the designed derivatives, M3 and M4 showed increased inhibitory efficiency against Mpro while also exhibiting significantly reduced cytotoxicity compared to the original masitinib molecule.

This study highlights the importance of molecular dynamics simulations and rational drug design in the development of potential treatments for COVID-19. The specific interactions identified between masitinib derivatives and the Mpro enzyme provide valuable insights for further research and development of antiviral therapies.