Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Abstract

With the rapid rate of SARS-CoV-2 Main protease (Mpro) structures deposition, a computational method that can combine all the useful structural features becomes crucial. This research focuses on the frequently occurring atoms and residues to find a generalized strategy for inhibitor design given a large amount of protein complexes from SARS-CoV in contrast to SARS-CoV-2 Mpro. By superposing large numbers of the ligands onto the protein template and grid box, we can analyse which part of the structure is conserved from position-specific interaction for both data sets for the development of pan-Mpro antiviral design. The difference in conserved recognition sites from the crystal structures can be used to determine specificity determining residues for designing selective drugs. We can display pictures of the imaginary shape of the ligand by unionising all atoms from the ligand. We also pinpoint the most probable atom adjustments to imitate the frequently found densities from the ligand atoms statistics. With molecular docking, Molecular Dynamics simulation, and MM-PBSA methods, a carbonyl replacement at the nitrile warhead (N5) of Paxlovid’s Nirmatrelvir (PF-07321332) was suggested. By gaining insights into the selectivity and promiscuity regions for proteins and ligands, crucial residues are highlighted, and the antiviral design strategies are proposed.

MD–Ligand–Receptor: A High-Performance Computing Tool for Characterizing Ligand–Receptor Binding Interactions in Molecular Dynamics Trajectories

“…MD simulations provide a microscopic view of the motion and interactions of molecules, enabling the analysis of structural changes, energetics, and other properties that are critical for understanding the action of drugs. Running MD simulations, especially of large systems for extended periods, poses a significant computational challenge [19][20][21][22][23], and the hardware resources and storage required for such simulations are considerable [24,25]. This becomes even more evident when large simulation trajectories are generated, which can result in data files of tens or even hundreds of gigabytes in size [26][27][28].…”

Exploring the Binding Effects of Natural Products and Antihypertensive Drugs on SARS-CoV-2: An In Silico Investigation of Main Protease and Spike Protein

“…Mpro's pivotal role in viral replication and the S protein's significance in mediating viral entry make them prime candidates for drug development. Computational investigations employing molecular docking and molecular dynamics (MD) simulations as well as virtual screening were instrumental in unveiling insights into the structural characteristics and dynamic behaviors of these proteins [12][13][14][15][16][17][18][19][20][21][22][23]. These studies aimed to identify novel compounds that can selectively inhibit Mpro's enzymatic activity and disrupt the binding of the S protein to its host cell receptor.…”