Functional and druggability analysis of the SARS-CoV-2 proteome

Abstract

The infectious coronavirus disease (COVID-19) pandemic, caused by the coronavirus SARS-CoV-2, appeared in December 2019 in Wuhan, China, and has spread worldwide. As of today, more than 46 million people have been infected and over 1.2 million fatalities. With the purpose of contributing to the development of effective therapeutics, we performed an in silico determination of binding hot-spots and an assessment of their druggability within the complete SARS-CoV-2 proteome. All structural, non-structural, and accessory proteins have been studied, and whenever experimental structural data of SARS-CoV-2 proteins were not available, homology models were built based on solved SARS-CoV structures. Several potential allosteric or protein-protein interaction druggable sites on different viral targets were identified, knowledge that could be used to expand current drug discovery endeavors beyond the currently explored cysteine proteases and the polymerase complex. It is our hope that this study will support the efforts of the scientific community both in understanding the molecular determinants of this disease and in widening the repertoire of viral targets in the quest for repurposed or novel drugs against COVID-19.

The SARS-CoV-2 replication-transcription complex is a priority target for broad-spectrum pan-coronavirus drugs

“…We used the PocketFinder function 6 in ICM (Molsoft, San Diego) to find potential druggable binding sites and assessed their druggability using SiteMap (Schrodinger, NY) 7 . The druggability evaluated with SiteMap was in general agreement with a previous work using a different method 3 and varied widely from poorly druggable, such as the catalytic site of the endoribonuclease nsp15 (Druggability score [Dscore] < 0.8), to highly druggable, such as a functionally uncharacterized ectopic site of the methyltransferase nsp14 (Dscore >1.0) (Figure 1a).…”

In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis

“…These selected proteins for the key targets such as RdRp (PDB ID: 6M71 ) and Mpro (PDB ID: 6Y2E ) have been deposited in protein data bank without any complexed or bound ligand. Hence, we felt the need to perform the SiteMap analysis for the selection of suitable binding or active sites for the proteins of interest [ 28 , 29 ]. Based on the volume of the pocket, enclosure, and the degree of hydrophobicity, the druggability assessment scores such as Dscore and SiteScore were calculated [30] to generate five binding sites ( Table 1 ) and Dscore were taken into consideration for a further selection of the suitable binding site and generation of a pharmacophore model.…”

Repurposing of Sitagliptin- Melittin Optimized Nanoformula against SARS-CoV-2; Antiviral Screening and Molecular Docking Studies

“…The protein is bounded to the irreversible Michael-acceptor peptidomimetic inhibitor, N3, covalently fitting at the substrate active site resembling 3CLpro natural substrate for preventing the enzyme catalytic activity ( Figure 7 ). The crystal complex consists of four sub-pockets (S1’-S4) corresponding to the four peptide partitions (P1’–P4) of natural substrate [ 70 ]. Several pocket residues are currently recognized for their significant role in binding of different ligands toward the 3CLpro active pocket [ 71 ].…”