Complete reconstruction of dasatinib unbinding pathway from c-Src kinase by supervised molecular dynamics simulation method; assessing efficiency and trustworthiness of the method.

Over the past years, rational drug design has gained lots of attention since employing it gave the world targeted therapy and more effective treatment solutions. Structure-based drug design (SBDD) is an excellent tool in rational drug design that takes advantage of accurate methods such as unbiased molecular dynamics (UMD) simulation for designing and optimizing molecular entities by understanding the binding and unbinding pathways of the binders. Supervised molecular dynamics (SuMD) simulation is a branch of UMD in which long-duration simulations are turned into short simulations, called replica, and a specific parameter is monitored throughout the simulation. In this work, we utilized this strategy to reconstruct the unbinding pathway of the anticancer drug dasatinib from its target protein, the c-Src kinase. Several unbinding events with valuable details were achieved. Then, to assess the efficiency and trustworthiness of the SuMD method, the unbinding pathway was also reconstructed by conventional UMD simulation, which uncovered some of the limitations of this method, such as limited sampling of the active site and finding the metastable states in the unbinding pathway. Furthermore, in times like these, when the world is desperate to find treatments for the Covid-19 disease, we think these methods are of exceptional value.Communicated by Ramaswamy H. Sarma.

Reconstruction of the unbinding pathways of noncovalent SARS-CoV and SARS-CoV-2 3CLpro inhibitors using unbiased molecular dynamics simulations.

The main protease (3CLpro) is one of the essential components of the SARS-CoVs viral life cycle, which makes it an interesting target for overpowering these viruses. Although many covalent and noncovalent inhibitors have been designed to inhibit this molecular target, none have gained FDA approval as a drug. Because of the high rate of COVID-19 pandemic development, in addition to laboratory research, we require in silico methods to accelerate rational drug design. The unbinding pathways of two SARS-CoV and SARS-CoV-2 3CLpro noncovalent inhibitors with the PDB IDs: 3V3M, 4MDS, 6W63, 5RF7 were explored from a comparative perspective using unbiased molecular dynamics (UMD) simulations. We uncovered common weak points for selected inhibitors that could not interact significantly with a binding pocket at specific residues by all their fragments. So water molecules entered the free binding S regions and weakened protein-inhibitor fundamental interactions gradually. N142, G143, and H163 are the essential residues, which cause key protein-ligand interactions in the binding pocket. We believe that these results will help design new potent inhibitors against SARS-CoV-2.

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

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.