Interactive Molecular Dynamics in Virtual Reality Is an Effective Tool for Flexible Substrate and Inhibitor Docking to the SARS-CoV-2 Main Protease

Abstract

The main protease (Mpro) of the SARS-CoV-2 virus is one focus of drug development efforts for COVID-19. Here, we show that interactive molecular dynamics in virtual reality (iMD-VR) is a useful and effective tool for creating Mpro complexes. We make these tools and models freely available. iMD-VR provides an immersive environment in which users can interact with MD simulations and so build protein complexes in a physically rigorous and flexible way. Recently, we have demonstrated that iMD-VR is an effective method for interactive, flexible docking of small molecule drugs into their protein targets ( 32160194 PLoS One 2020 15 e0228461 ). Here, we apply this approach to both an Mpro inhibitor and an oligopeptide substrate, using experimentally determined crystal structures. For the oligopeptide, we test against a crystallographic structure of the original SARS Mpro. Docking with iMD-VR gives models in agreement with experimentally observed (crystal) structures. The docked structures are also tested in MD simulations and found to be stable. Different protocols for iMD-VR docking are explored, e.g., with and without restraints on protein backbone, and we provide recommendations for its use. We find that it is important for the user to focus on forming binding interactions, such as hydrogen bonds, and not to rely on using simple metrics (such as RMSD), in order to create realistic, stable complexes. We also test the use of apo (uncomplexed) crystal structures for docking and find that they can give good results. This is because of the flexibility and dynamic response allowed by the physically rigorous, atomically detailed simulation approach of iMD-VR. We make our models (and interactive simulations) freely available. The software framework that we use, Narupa, is open source, and uses commodity VR hardware, so these tools are readily accessible to the wider research community working on Mpro (and other COVID-19 targets). These should be widely useful in drug development, in education applications, e.g., on viral enzyme structure and function, and in scientific communication more generally.

Discovery of SARS-CoV-2 MproPeptide Inhibitors from Modelling Substrate and Ligand Binding

“…It should be noted that iMD-VR has successfully produced accurate docked structures of various drug-viral enzyme complexes, including oligopeptide-and inhibitor-M pro complexes. 44,45 Throughout both the explicit-solvent MD of all 11 substrates and the implicit-solvent MD simulations of iMD-VR structures of s01, s02, and s05, all substrates remained tightly bound in the active site (see backbone RMSD, and root mean square fluctuation or RMSF analyses in Figures S2.7-10). Backbone stability is maintained especially in the central region of the substrates, with only the N-and C-terminal residues showing substantial flexibility.…”

Benchmarking the Ability of Common Docking Programs to Correctly Reproduce and Score Binding Modes in SARS-CoV-2 Protease Mpro

“… 47 , 69 Thus far, several docking approaches have been employed to screen M pro for potential drugs in virtual screening and drug repurposing campaigns, including Glide, 7 , 10 , 13 , 17 , 18 , 70 − 72 Autodock, 11 , 13 , 73 , 74 Autodock Vina, 11 , 13 , 14 , 19 , 71 , 73 , 75 , 76 Surflex, 77 PLANT, 78 DockThor, 76 fast pulling of ligands, 14 deep docking, 70 algebraic topology and deep learning, 79 and virtual reality-based docking. 16 However, to the best of our knowledge, no rigorous benchmark study addressing the ability of such docking tools to reproduce and correctly rank known ligand binding modes has been published, in spite of the known inherent challenges in docking. 80 − 83 …”

Molecular docking, binding mode analysis, molecular dynamics, and prediction of ADMET/toxicity properties of selective potential antiviral agents against SARS-CoV-2 main protease: an effort toward drug repurposing to combat COVID-19

“…Several literature evidences are implicating that SARS-CoV-2 M pro could be used for screening purposes to predict the binding affinity of the approved drugs, natural inhibitors, and those in clinical trials [ 5 , 42 – 44 ]. The binding stability of an α-ketoamide inhibitor O6K or 13b as reference control inside the SARS-CoV-2 M pro was carried out to assess affinity score and determine theoretically the possible and probable active site residues involved in the formation of complex, which was found consistent with our observation [ 44 – 47 ].…”

“…The oxo group at the 14th position and the carbonyl oxygen of carboxylic acid at the second position of icosahydropicene-2-carboxylic acid core nucleus of GA exhibited conventional hydrogen bond interactions with the amino group of GLN189 (3.01 and 2.19 Å, respectively). Further, hydrophobic alkyl interactions were observed between the icosahydropicene-2-carboxylic acid core nucleus methyl groups of GA with CYS145 ( Several literature evidences are implicating that SARS-CoV-2 M pro could be used for screening purposes to predict the binding affinity of the approved drugs, natural inhibitors, and those in clinical trials [5,[42][43][44]. The binding stability of an α-ketoamide inhibitor O6K or 13b as reference control inside the SARS-CoV-2 M pro was carried out to assess affinity score and determine theoretically the possible and probable active site residues involved in the formation of complex, which was found consistent with our observation [44][45][46][47].…”

“…Further, hydrophobic alkyl interactions were observed between the icosahydropicene-2-carboxylic acid core nucleus methyl groups of GA with CYS145 ( Several literature evidences are implicating that SARS-CoV-2 M pro could be used for screening purposes to predict the binding affinity of the approved drugs, natural inhibitors, and those in clinical trials [5,[42][43][44]. The binding stability of an α-ketoamide inhibitor O6K or 13b as reference control inside the SARS-CoV-2 M pro was carried out to assess affinity score and determine theoretically the possible and probable active site residues involved in the formation of complex, which was found consistent with our observation [44][45][46][47]. The Cys145-His41 catalytic dyad and amino acid residues CYS145, SER144, and GLY143 (collectively referred to as catalytic center), which are involved in the creation of an oxyanion hole, are essential for stabilizing the transition process during proteolysis [48].…”