Unraveling the unbinding pathways of SARS-CoV-2 Papain-like proteinase known inhibitors by Supervised Molecular Dynamics simulation

Abstract

The COVID-19 disease has infected and killed countless people all over the world since its emergence at the end of 2019. No specific therapy for COVID-19 is not currently available, and urgent treatment solutions are needed. Recent studies have found several potential molecular targets, and one of the most critical proteins of the SARS-CoV-2 virus work machine is the Papain-like protease (Plpro). Potential inhibitors are available, and their X-ray crystallographic structures in complex with this enzyme have been determined recently. However, their activities against this enzyme are insufficient and need to be characterized and improved to be of clinical values. Therefore, in this work, by utilizing the Supervised Molecular Dynamics (SuMD) simulation method, we achieved multiple unbinding events of Plpro inhibitors, GRL0617, and its derivates, and captured and understood the details of the unbinding pathway. We found that residues of the BL2 loop, such as Tyr268 and Gln269, play major roles in the unbinding pathways, but the most important contributing factor is the natural movements and behavior of the BL2 loop, which can control the entire process. We believe that the details found in this study can be used to refine and optimize potential inhibitors like GRL0617 and design more efficacious inhibitors as a treatment for the SARS-CoV-2 virus.

Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors

“…Moreover, similar to cooperativity in systems containing multiple ligand binding sites, cooperativity in monomeric single-site enzymes can be explained by protein conformational changes [ 44 ]. PL pro flexibility and conformational changes were investigated in the ligand-free and ligand-bound states to characterize the overall protein dynamics [ 45 , 46 ]. These studies indicated that residues of the blocking loop 2 (BL2) play major roles in the unbinding pathways.…”

“…Specifically, residues Asn267, Gln269, and most importantly Tyr268, account for most of this motion, which resembles the opening and closing of the loop [ 45 ]. Simulations showed that the BL2 loop in SARS-CoV-2 PL pro is highly stabilized by ligand binding [ 46 ]. Of note, the sidechain and backbone rotation of Tyr268 is reduced by a hydrogen bond and strong van der Waals interactions with the ligand.…”

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“…Supervised MD simulations were employed to investigate the unbinding pathways of GRL0617 and its derivates from PLpro. 168 Sun et al applied MD simulations and topological and electrostatic analyses to study the effects of palmitoylation on an E protein pentamer. Their results indicated that the structure of the palmitoylated E protein pentamer was more stable while the loss of palmitoylation caused the pore radius reduced and even collapsed, which might help the drug design for the treatment of COVID-19.…”

Inhibitor induced conformational changes in SARS-COV-2 papain-like protease

“…1 C). PLP_Snyder530 has an acryloyl amino group instead of a single amine group on the benzamide moiety, in comparison with GRL-0617 and XR8-89, which slightly reduces this ligand’s potency 23 . On the other hand, ligands that have an N,N’-diacetylhydrazine group could access the BL2’s region to the active site and improve the activity against PL pro 24 .…”