Exploring the SARS-CoV-2 Proteome in the Search of Potential Inhibitors via Structure-Based Pharmacophore Modeling/Docking Approach

Abstract

To date, SARS-CoV-2 infectious disease, named COVID-19 by the World Health Organization (WHO) in February 2020, has caused millions of infections and hundreds of thousands of deaths. Despite the scientific community efforts, there are currently no approved therapies for treating this coronavirus infection. The process of new drug development is expensive and time-consuming, so that drug repurposing may be the ideal solution to fight the pandemic. In this paper, we selected the proteins encoded by SARS-CoV-2 and using homology modeling we identified the high-quality model of proteins. A structure-based pharmacophore modeling study was performed to identify the pharmacophore features for each target. The pharmacophore models were then used to perform a virtual screening against the DrugBank library (investigational, approved and experimental drugs). Potential inhibitors were identified for each target using XP docking and induced fit docking. MM-GBSA was also performed to better prioritize potential inhibitors. This study will provide new important comprehension of the crucial binding hot spots usable for further studies on COVID-19. Our results can be used to guide supervised virtual screening of large commercially available libraries.

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation

“…After proteolytic cleavage, pp1a and pp1b yield 16 non-structural proteins (nsp1 to nsp16), including PL pro and M pro . The virus encodes other proteins, including ORF10 and nsp7b ( 49 ). These proteins can also form complexes, such as the nsp7/nsp8/Pol hetero-oligomeric complex, the spike glycoprotein/human angiotensin I-converting enzyme 2 (hACE2) hetero-oligomeric complex, the nsp7/nsp8 hetero-oligomeric complex, the nsp10/nsp14 hetero-oligomeric complex and the nsp10/nsp16 hetero-oligomeric complex ( 49 ).…”

“…The virus encodes other proteins, including ORF10 and nsp7b ( 49 ). These proteins can also form complexes, such as the nsp7/nsp8/Pol hetero-oligomeric complex, the spike glycoprotein/human angiotensin I-converting enzyme 2 (hACE2) hetero-oligomeric complex, the nsp7/nsp8 hetero-oligomeric complex, the nsp10/nsp14 hetero-oligomeric complex and the nsp10/nsp16 hetero-oligomeric complex ( 49 ). The SARS-CoV-2 proteome could be applied to IgG and IgM response profiling, as these antibodies have been found to bind specifically to the N and S proteins ( 95 ).…”

Microsecond MD Simulation and Multiple-Conformation Virtual Screening to Identify Potential Anti-COVID-19 Inhibitors Against SARS-CoV-2 Main Protease

“…For the molecular modeling calculations, the crystal structure SARS-CoV-2 main protease (M pro /3CL pro ) with the PDB ID: 6LU7 is prepared utilizing the standard protocol of the protein preparation wizard (Jin et al, 2020 ). The co-crystal ligand N3 is covalently bound with an active site amino acid Cys145, and in preparation we manually break the covalent bond and fill the open valance (Culletta et al, 2020 ; Wang, 2020 ). Here, the missing atoms and partial charges (charge alteration shown in Supplementary Figures 1a,b ) are added, and the missing side-chain atoms and bond orders are refined (Sastry et al, 2013 ).…”

Immunoproteasome and Non-Covalent Inhibition: Exploration by Advanced Molecular Dynamics and Docking Methods

“…Both 20S subunits, murine and human, share a sequence identity of more than 90%, and the few nonidentical residues are external to the active sites. As reported in the literature, in the case of covalent cocrystallized inhibitors [ 25 , 26 ], the reactive residue at the catalytic site was rebuilt after removing the covalent inhibitor by breaking the covalent bond and filling in the open valence. In this case, the involved residue was Thr1.…”