Can Natural Products Stop the SARS-CoV-2 virus? a Docking and Molecular Dynamics Study of a Natural Product Database

Abstract

Background: The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. Methodology: A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Conclusion: Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.

Searching and designing potential inhibitors for SARS-CoV-2 Mpro from natural sources using atomistic and deep-learning calculations

“…65 However, the obtained affinities were smaller than the top-lead compounds of Natural Product Arlats, which the docking energies adopted in the range from À8.2 to À9.4 kcal mol À1 . 69 Unbinding ligand to rene binding affinity AutoDock Vina uses numerous approximations such as acquired united-atom model, rigid receptor, and rarely tested ligand positions, the obtained results are thus required to rene via MD simulations. 23,58,71 In this work, FPL simulations were employed to rene the docking outcome, 58 because the approach formed a good correlation coefficient to the respective experiments with a value, R FPL , ranging from À0.74 AE 0.11 to À0.76 AE 0.01.…”

A new glimpse on the active site of SARS-CoV-2 3CLpro, coupled with drug repurposing study

“…The structure of the SARS-CoV-2 3CLpro was taken from Reference [ 26 ]. It was extracted from 900 ns molecular dynamics simulation, as a representative structure of the dominant conformation, with a population above 86%.…”

“…Here, Cys145 has a role of a nucleophile in the first step of the proteolysis, while His41 is the base catalyst [ 25 ]. The existence of allosteric binding sites in the groove between domains II and III has been proposed, with the possibility to stop the dimerization and prevent enzyme maturation [ 26 , 27 ].

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“…Khan et al [ 32 ] performed docking and molecular dynamics simulations to propose paritaprevir and raltegravir as lead candidates for inhibition of SARS-CoV-2 3CLpro, and dolutegravir and bictegravir for inhibition of 2′-O-ribose mathylotransferase. Alternative approach seeks inspiration from nature, from microbial natural products [ 26 ] to phytocompounds [ 33 – 36 ], to pinpoint active compounds useful for treatment of COVID-19 patients.…”

Proposition of a new allosteric binding site for potential SARS-CoV-2 3CL protease inhibitors by utilizing molecular dynamics simulations and ensemble docking

“…Additionally, Novak et al. performed virtual screening of molecules from the Natural Product Atlas and molecular dynamics simulations of the most potent 3CLpro inhibitor, demonstrating a similar binding potential for a variety of inhibitors for the catalytic and the allosteric groove binding sites (Novak et al., 2021 ). An alternative way of choosing a virtual screening target is to identify the most important virus-host interactions and try to find ligands which could bind to their interface and disrupt these interactions (Gollapalli et al., 2020 ).…”