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

Abstract

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.

Mutational Impacts on the N and C Terminal Domains of the MUC5B Protein: A Transcriptomics and Structural Biology Study

“…We obtained MD simulation trajectories of the targeted MUC5B WT and MT domains after a period of 100 ns. The backbone RMSD of each WT and MT was computed using the GROMACS default function g_rms . The mutations in targeted structures, let us call them the N and C domains, showed slight deviations relative to their WT protein (Figure ).…”

“…The backbone RMSD of each WT and MT was computed using the GROMACS default function g_rms. 47 The mutations in targeted structures, let us call them the N and C domains, showed slight deviations relative to their WT protein ( Figure 4 ). The WT protein shows minor fluctuations in the initial 25 ns and then stabilizes until the last frame of the simulation, maintaining an RMSD value of 1.3 nm.…”

In silico formulation of a next-generation multiepitope vaccine for use as a prophylactic candidate against Crimean-Congo hemorrhagic fever

“…The binding interactions between proteins and desired ligands can be revealed by molecular docking studies [ 66 ]. Toll-like receptors 3/8 (TLR-3/8) play a crucial role in CCHF viral infection [ 48 , 67 ], and TLR4 has critical functioning for initiation of viral pathogenesis to induce inflammatory response [ 68 ].…”

Identification of natural Rutaecarpine as a potent tobacco mosaic virus (TMV) helicase candidate for managing intractable plant viral diseases

“…The TMV helicase binding site coordination was defined with a box (active site; x = 15.030, y = −28.172, and z = −14.550), and grid spacing was set at 0.375 Å (20 × 18 × 18 xyz points); other parameters take the default form. Each ligand docking pose was set by default to nine poses, and the lowest affinity was output as the final result (Autodock Vina 1.2.1) 32,33 …”