Search for Novel Potent Inhibitors of the SARS-CoV-2 Papain-like Enzyme: A Computational Biochemistry Approach

Abstract

The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design.

Deciphering the Molecular Interaction Process of Gallium Maltolate on SARS-CoV-2 Main and Papain-Like Proteases: A Theoretical Study

“…A series of bioinformatics protocols were implemented to validate and refine the structural models using the Protein Preparation Wizard [54] from the Schrödinger suite, adopting the OPLS force field [55] to ensure computational modeling fidelity. The binding sites were inferred from the centroid of the co-crystallized ligands [56][57][58], which is a critical determinant for the generation of the grid maps by AutoGrid 4.0. These maps were constructed with a resolution of 0.375 Å across a 60 3 -point grid, establishing the spatial context for the docking calculations.…”

“…PL pro is a monomeric enzyme characterized by four subdomains: the N-terminal ubiquitin-like domain (Ubl), the α-helical thumb domain, the β-stranded finger domain, and the palm domain. The catalytic triad responsible for PL pro 's enzymatic activity includes Cys111, His272, Tyr264, Tyr268, and Asp286 [53,56,67,68]. PL pro is highly similar to its counterpart in the SARS-CoV virus, sharing conserved structural features and an impressive 82% sequence identity.…”

“…The S3-S4 subsites within the substrate binding cleft are critical for accommodating key inhibitor groups, such as the zinc-binding moiety of TTT. Inhibitors targeting cysteine residues in the zinc-binding domain are particularly promising for drug development [53,56,67].…”