Protein reliability analysis and virtual screening of natural inhibitors for SARS-CoV-2 main protease (M^pro) through docking, molecular mechanic & dynamic, and ADMET profiling

Abstract

Due to an outbreak of COVID-19, the number of research papers devoted to in-silico drug discovery of potential antiviral drugs is increasing every day exponentially. Still, there is no specific drug to prevent or treat this novel coronavirus (SARS-CoV-2) disease. Thus, the screening for a potential remedy presents a global challenge for scientists. Up to date over a hundred crystallographic structures of SARS-CoV-2 M pro have been deposited to Protein Data Bank. With many known proteins, the demand for a reliable target has become higher than ever, so as the choice of an efficient computational methods. Therefore, in this study comparative methods have been used for receptor-based virtual screening, targeting 9 selected structures of viral M pro. Reliability analyses followed by re-docking of the specific co-crystallized ligand provided the best reproductivity for structures with PDB ID 6LU7, 6Y2G and 6Y2F. The influence of crystallographic water on an outcome of a virtual screening against selected targets was also investigated. Once the most reliable targets were selected, the library of easy purchasable natural compounds were retrieved from the MolPort database (10,305 compounds) and docked against the selected M pro proteins. To ensure the efficiency of the selected compounds, binding energies for top-15 hit ligands were calculated using Molecular Mechanics as well as their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted. Based on predicted binding energies and toxicities, top-5 compounds were selected and subjected to Molecular Dynamics simulation and found to be stable in complex to act as possible inhibitors for SARS-CoV-2.

Structure-based identification of SARS-CoV-2 main protease inhibitors from anti-viral specific chemical libraries: an exhaustive computational screening approach

“…RMSD of the protein backbone and ligand was noticed within 2 and 5 Å, respectively. The RMSF of M pro amino acids was to be fluctuated around 1 Å. Kapusta et al [ 45 ] explored the virtual screening of MolPort database and proposed about fifteen promising M pro modulators. However, they have reported higher RMSD score (~ 6 to 10 Å) for M pro protein backbone bound with few molecules.…”

“…A number of recent studies have already been performed to estimate the binding free energy through MM-GBSA approach of virtually screened M pro modulators. Proposed M pro molecules reported by Kapusta et al [ 45 ] demonstrated the highest negative MM-GBSA-based binding free energy value of about −60 kcal/mol. Choudhary et al also screened a few interesting M pro inhibitors and calculated binding free energy using the MM-GBSA approach, and the value was varied in the range of about −50 to −80 kcal/mol.…”

Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug

“…This large body of knowledge, accumulated in a short time thanks to the enormous collective effort of the scientific community, on the structure and function of has stimulated a number of works and methodology for in silico drug design [ 12 , 13 , 14 , 15 , 16 ]. Recently drug repositioning has been recognized as an alternative approach that explores new indications for approved (or also abandoned) drugs.…”

Repurposing simeprevir, calpain inhibitor IV and a cathepsin F inhibitor against SARS-CoV-2 and insights into their interactions with Mpro

“…Using M pro as the target, our group had recently reported a subset of drugs from the SuperDrug2 database which showed potential to be used against SARS-CoV-2 (Arun et al, 2020). Many recent studies have reported the identification of hit compounds against the M pro of SARS-CoV-2 using computational methods (Fakhar et al, 2020;Ghosh et al, 2020;Ibrahim et al, 2020;Kapusta et al, 2020;Sharma et al, 2020).…”