Detection of Binding Sites on SARS-CoV-2 Spike Protein Receptor-Binding Domain by Molecular Dynamics Simulations in Mixed Solvents

Abstract

The novel SARS-CoV-2 uses ACE2 (Angiotensin-Converting Enzyme 2) receptor as an entry point. Insights on S protein receptor-binding domain (RBD) interaction with ACE2 receptor and drug repurposing has accelerated drug discovery for the novel SARS-CoV-2 infection. Finding small molecule binding sites in S protein and ACE2 interface is crucial in search of effective drugs to prevent viral entry. In this study, we employed molecular dynamics simulations in mixed solvents together with virtual screening to identify small molecules that could be potential inhibitors of S protein -ACE2 interaction. Observation of organic probe molecule localization during the simulations revealed multiple sites at the S protein surface related to small molecule, antibody, and ACE2 binding. In addition, a novel conformation of the S protein was discovered that could be stabilized by small molecules to inhibit attachment to ACE2. The most promising binding site on RBD-ACE2 interface was targeted with virtual screening and top-ranked compounds (DB08248, DB02651, DB03714, and DB14826) are suggested for experimental testing. The protocol described here offers an extremely fast method for characterizing key proteins of a novel pathogen and for the identification of compounds that could inhibit or accelerate spreading of the disease.

Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein

“…Pyrimidine (Py), acetonitrile, and isopropanol were used to discover possible docking niches on the interface between RBD and ACE2, and to inspire the drug design of antagonists or antibodies. [ 57 ] Py showed the most relevant volumetric maps within the RBD that spans from residue Gln498 to residue Tyr505. Knowledge of these types of interactions, in conjunction with the molecular mechanics with generalized Born surface area solvation (MM‐GBSA) analysis, leads drug design processes and virtual screening in concordance with experimental data from antibodies, with the data suggesting a set of new molecules (DB02651, DB03714, DB08248, and DB14826) as possible RBD interaction modulators.…”

Molecular dynamics simulations reveal the importance of conformational changes, glycosylation, mutations, and drug repurposing for the Sars-Cov-2 spike protein

“…Pyrimidine (Py), acetonitrile, and isopropanol were used to discover possible docking niches on the interface between RBD and ACE2, to inspire the drug design of antagonists or antibodies. [44] Py showed the most relevant volumetric maps within the RBM that spans from residue Gln498 to residue Tyr505. Knowledge of these types of interactions, in conjunction with molecular mechanics with generalised Born surface area solvation (MM-GBSA) analysis, lead drug design processes and virtual screening in concordance with experimental data from antibodies, has suggested a set of new molecules (DB02651, DB03714, DB08248 and DB14826) as possible RBD interaction modulators.…”

Sdfconf: A Novel, Flexible, and Robust Molecular Data Management Tool

“…This was done by measuring distances between chosen atoms. 16,18 Rauhamaki et al used sdfconf to generate a simple pharmacophore filter to refine docked conformations. Sdfconf was used to select only conformations without hydrophobic groups in proximity of a certain side chain atom.…”

“…More examples of how sdfconf has been utilized in research can be found from recent studies. − For example, classification of molecules/conformations based on any property and importing and exporting data into metafields have been used extensively. Kurkinen et al used sdfconf to calculate the average geometric centroids for the top-ranked docking poses .…”

“…Jokinen et al and Juvonen et al employed sdfconf to filter docking poses to find those conformations that have the potential to form a hydrogen bond with a certain atom in amino acid. This was done by measuring distances between chosen atoms. , Rauhamäki et al used sdfconf to generate a simple pharmacophore filter to refine docked conformations. Sdfconf was used to select only conformations without hydrophobic groups in proximity of a certain side chain atom .…”