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 22 million people have been infected, with almost 800,000 fatalities. With the purpose of contributing to the development of effective therapeutics, this work provides an overview of the viral machinery and functional role of each SARS-CoV-2 protein, and a thorough analysis of the structure and druggability assessment of the viral proteome. All structural, non-structural, and accessory proteins of SARS-CoV-2 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 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.

Influence of the Structural Accuracy of Homology Models on Their Applicability to Docking-Based Virtual Screening: The β2 Adrenergic Receptor as a Case Study

“…However, it is worth noting that it is generally recognized that the effectiveness of GPCR models as platforms for virtual screening significantly improves when the models are optimized in complex with a prototypical ligand, for instance through molecular dynamics or conformational searches, or when experimental information is incorporated in the screening, for instance through the application of filters or fingerprints meant to capture plausible receptor-ligand interactions. 25,50,[54][55][56] Indeed, a recent article from Loo and coworkers, in which homology models of eight different GPCRs were evaluated for their virtual screening performance, pointed out that geometrically optimizing the models around the structure of a docked ligand significantly improved their performance in docking-based virtual screening. The authors proved this by docking into their homology models the ligand co-crystallized with a reference structure of the modeled receptor through a procedure that accounts for the flexibility of both ligands and receptors (induced fit docking).…”

“…Overall, these assessments, together with additional studies conducted by other investigators, highlighted that high accuracy can be achieved for models based on closely related templates, while only macroscopic folding could be predicted for models based on distant templates. [20][21][22][23][24][25][26] Along these lines, in a recent paper, we conducted a systematic controlled homology modeling study by building models of the β 2 AR based on 23 different structural templates. This study highlighted a significant correlation between template/target receptor sequence identity and accuracy of the resulting models.…”

Lipid polymer hybrid nanocarriers as a combinatory platform for different anti-SARS-CoV-2 drugs supported by computational studies

“…Among the SARS-CoV-2 proteins, the papain-like protease (PLpro, nsp3 domain) shows increasing importance in SARS-CoV-2 drug ability. 62 In the current work, viral papain-like cysteine protease (PLpro, NSP3) was selected as a target protein because it represents a promising target for the development of antiviral drugs (PDB: ID:6wuu 63 ) against SARS-CoV-2. To validate our study, the docked co-crystallized ligand exhibited bonding interaction very similar to the reported co-crystallized complex.…”

Inverted repeats in coronavirus SARS-CoV-2 genome and implications in evolution

“…ORF1ab encodes replicase polyproteins required for viral RNA replication and transcription [7,5]. Nonstructural protein 1 (nsp1) likely inhibits host translation by interacting with 40S ribosomal subunit, leading to host mRNA degradation through cleavage near their 5'UTRs.…”