VIR251 / UT Health San Antonio, Wroclaw University of Science and Technology - LARVOL DELTA

Integration of computational and experimental techniques for the discovery of PLpro covalent inhibitors. When large virtual screening and rational design meet. (PubMed, Eur J Med Chem) - "While 3CLpro has been the main target of many potential antivirals including nirmatrelvir (active ingredient of Paxlovid), PLpro has proven to be more challenging to target and only a handful of inhibitors have been disclosed...Combining our experience with 3CLpro covalent inhibitors with our expertise in structure-based covalent drug discovery, we rationally designed PLpro inhibitors achieving a maximum potency (IC50) of 13 μM through fusion of GRL0617 and VIR-251 PLpro inhibitors...We report herein our investigations including rational design, virtual screening, synthesis of selected structures and in vitro assays leading to novel PLpro inhibitors. Surprisingly, these two very distinct approaches led to structures with similar features."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

A computational essential dynamics approach to investigate structural influences of ligand binding on Papain like protease from SARS-CoV-2. (PubMed, Comput Biol Chem) - "Next, based on molecular docking results, ZINC000000596945, ZINC000064033452 and VIR251 (control molecule) were subjected to molecular dynamics simulation. The study evaluated global and essential dynamics analyses utilising principal component analyses, dynamic cross-correlation matrix, free energy landscape and time-dependant essential dynamics to predict the structural changes observed in PLpro upon ligand binding in a simulated environment. The MM/PBSA-based binding free energy calculations of the two selected molecules, ZINC000000596945 (-41.23 ± 3.70 kcal/mol) and ZINC000064033452 (-25.10 ± 2.65 kcal/mol), displayed significant values which delineate them as potential inhibitors of PLpro from SARS-CoV-2."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Targeted Protein Degradation

Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease. (PubMed, Int J Mol Sci) - "In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys), through a Michael addition reaction...Finally, due to Cys-S negative charge redistribution over the bound ligand, proton transfer from the initially protonated His is favored, finally leading to an irreversibly modified Cys and a restored His. These results elucidate the selectivity of Cys to enable formation of a covalent bond, even if a weak proton acceptor is available, as His."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

In Silico Elucidation of Potent Inhibitors and Rational Drug Design against SARS-CoV-2 Papain-like Protease. (PubMed, J Phys Chem B) - "Here, we employed the all-atom molecular dynamics (MD) simulations and binding free energy calculations based on MM-PB(GB)SA and SIE methods to elucidate and compare the binding behaviors of five inhibitors derived from peptidomimetic inhibitors (VIR250 and VIR251) and naphthalene-based inhibitors (GRL-0617, compound 3, and compound Y96) against SARS-CoV-2 PLpro. Furthermore, the hydrophobic interactions with residues at P1-P3 sites can be increased by enlarging the nonpolar moieties (e.g., ethene) at the N-terminal of VIR250. We expect that the structural data obtained will contribute to the development of new PLpro inhibitors with more inhibitory potency for COVID-19."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases