Computational Discovery of Novel Imidazole Derivatives as Inhibitors of SARS-CoV-2 Main Protease: An Integrated Approach Combining Molecular Dynamics and Binding Affinity Analysis

Abstract

One of the most pressing challenges associated with SARS treatment is the emergence of new variants that may be transmissible, causing more severe disease or being resistant to the current standard of treatment. This study aimed to identify potential drug candidates from novel imidazole derivatives against SARS-CoV-2 main protease (Mpro), a crucial drug target for treating viral infection, using a computational approach that integrated molecular docking and dynamics simulation. In this study, we utilized AutoDock Vina within the PyRx workspace for molecular docking analysis to explore the inhibitory effects of the compounds on the Mpro, a drug target for SARS-CoV-2. The ADMET properties of these compounds, including absorption, distribution, metabolism, excretion, and toxicity, were evaluated using the SwissADME and ADMETLab servers. Each of the 18 compounds that were tested demonstrated strong binding affinities towards Mpro, with imidazolyl–methanone C10 showing the most significant binding affinity. Moreover, pyridyl–imidazole C5, thiophenyl–imidazole C1, and quinoline–imidazole C14 displayed binding affinities of −8.3, −8.2, and −7.7 Kcal/mol, respectively. These compounds interacted with specific amino acid residues (HIS A:41—CYS A:145) within the Mpro protein. To assess the stability of the ligand with the best binding affinity, molecular dynamics (MD) simulations were conducted using Schrodinger software, which revealed its stability over the simulation period. The study provides valuable insights into the potential of imidazole derivatives as SARS-CoV-2 Mpro inhibitors. All compounds including C10 display promising characteristics and hold potential as drug candidates for SARS-CoV-2. However, further optimization and experimental validation of these compounds are necessary to advance their development as effective therapeutics against viral infections.