Drug Binding Dynamics of the Dimeric SARS-CoV-2 Main Protease, Determined by Molecular Dynamics Simulation

Abstract

<div> <div> <div> <p>We performed molecular dynamics simulation of the dimeric SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) main protease (Mpro) to examine the binding dynamics of small molecular ligands. Seven HIV inhibitors, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir, were used as the potential lead drugs to investigate access to the drug binding sites in Mpro. The frequently accessed sites on Mpro were classified based on contacts between the ligands and the protein, and the differences in site distributions of the encounter complex were observed among the ligands. All seven ligands showed binding to the active site at least twice in 28 simulations of 200 ns each. We further investigated the variations in the complex structure of the active site with the ligands, using microsecond order simulations. Results revealed a wide variation in the shapes of the binding sites and binding poses of the ligands. Additionally, the C-terminal region of the other chain often interacted with the ligands and the active site. Collectively, these findings indicate the importance of dynamic sampling of protein- ligand complexes and suggest the possibilities of further drug optimisations. <br></p><p><br></p><p><br> </p><div> <div> <div> <p>Raw trajectory data analysed in this paper and movie examples are available at the zenodo repository.<br></p> </div> </div> </div> </div> </div> </div>

High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

“…Two main research groups, DE Shaw Research (DESRES) and RIKEN Center for Biosystems Dynamics Research, recently released multi microseconds MD simulations of the M pro dimer. 6,7 These MD conformational ensembles both used non-polarizable force fields (n-PFF) such as DES-Amber 10 and AMBER14ff 11 . Although they are of great help for the scientific community, conventional MD (cMD) simulation results are however limited by the daunting complexity of M pro 's conformational space, which requires very large computational ressources.…”

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

“…A 10 µs simulation data on dimer of 3CL pro was obtained MDGRAPE-4A, at RIKEN BDR, JAPAN [41]. However, only monomer data was used from this 10 µs as the simulations performed MSM analysis is widely used for significant sampling of the MD simulation data [50][51][52][53][54].…”

“…shows the presence of covalently bound inhibitor N3 in its active site ( Figure 1) [35]. This structure has been widely used by the research community for performing molecular docking and simulation studies [39][40][41][42]. The 3D coordinates for the apo form of 3CL pro were obtained from the PDB ID 6LU7 [35].…”

“…MD simulations were performed for a cumulative of 150 ns for the apo 3CL pro . An open source 10 μs MD simulation data of 3CL pro dimer was obtained from the simulations performed on MDGRAPE-4A supercomputing cluster located at RIKEN BDR, Japan [41] were docked against the FDA approved and SWEETLEAD drug database. The best ranked drugs obtained from both these approaches belonged to the class of anti-bacterial and anti-viral drugs.…”

High-Resolution Mining of SARS-CoV-2 Main Protease Conformational Space: Supercomputer-Driven Unsupervised Adaptive Sampling

“…However, while more than one hundred M pro structures exists and massive efforts to discover successful inhibitor are underway, computational approaches involving virtual screening as well as Molecular Dynamics are involved to help experimenters to in silico optimize their millions of test molecules. [6][7][8][9] Molecular Dynamics (MD) is a powerful tool which aims at improving the understanding of structural and dynamical features of complex biological systems. It also improves the ability to properly identify promising protein inhibitors.…”