Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach

The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2. [Display omitted] ●Several studies have confirmed the main protease (Mpro) of the SARS-CoV-2 as a promising therapeutic target.●We scanned for small molecules from the ChemBridge database that could interact with the active site residues of the Mpro, among which the Thr24, His41, Met165, and Pro168 residues were highly involved in bonding.●Molecular dynamics simulation further explored molecular docking-based predicted interactions, revealing promising interactions among protein-ligand complexes observed through stable RMSDs and RMSFs, PCA plots, and hydrogen bonding analysis.●We propose five compounds with ChemBridge IDs (12196498, 12259240, 12347415, 12361793, 12414646) with a stronger affinity towards Mpro.