SARS-CoV-2 3D database: understanding the coronavirus proteome and evaluating possible drug targets

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly growing infectious disease, widely spread with high mortality rates. Since the release of the SARS-CoV-2 genome sequence in March 2020, there has been an international focus on developing target-based drug discovery, which also requires knowledge of the 3D structure of the proteome. Where there are no experimentally solved structures, our group has created 3D models with coverage of 97.5% and characterized them using state-of-the-art computational approaches. Models of protomers and oligomers, together with predictions of substrate and allosteric binding sites, protein-ligand docking, SARS-CoV-2 protein interactions with human proteins, impacts of mutations, and mapped solved experimental structures are freely available for download. These are implemented in SARS CoV-2 3D, a comprehensive and user-friendly database, available at https://sars3d.com/. This provides essential information for drug discovery, both to evaluate targets and design new potential therapeutics.

Keywords: SARS-CoV-2 3D database; SARS-CoV-2 drug targets; SARS-CoV-2 proteome modelling; drug discovery; proteome analysis.

Figure 1

Statistical analysis of modelled proteome. (A) The total percentage sequence coverage of experimentally solved structures deposited in RSCB (Research Collaboratory for Structural Bioinformatics) is represented in cyan, whereas the total percentage coverage of each modelled structure is shown above it in red. (B) MolProbity scores for all modelled SARS-CoV-2 structures deposited in the SARS-CoV-2 3D database.

Figure 2

Four modelled oligomeric targets selected from the SARS-CoV-2 proteome. (A) Nsp14 (white-grey) and Nsp10 (green). The zinc ions are shown as silver spheres, and the magnesium ion as a green sphere. The SAH ligand is represented in magenta pink, and the G3A in green. Binding interactions of both ligands in the Nsp14 binding sites are represented as dashed lines highlighted in black. (B) Homo-pentameric model of Envelope protein E with each protomer indicated in a different colour. The membrane is represented as a red/blue circular structure. (C) Homodimeric model of the membrane protein M, with protomers coloured in green and white. The membrane is represented as a red/blue circular structure. (D) The structure of the Nsp1 model, coloured dark blue and encircled, complexed with the 40S ribosome (a hetero-35-mer) with the 35 proteins coloured differently.

Figure 3

Website interface front page and result page: (A) Home page: the jumbotron at the top left represents the main ideas of the database. The query options such as a table or sunburst are represented below. (B) Results page. The top represents a brief description of the target genes with external links to other modelling pipelines: MolStar viewer for protein visualizations, Fpocket table and UniProt viewer for sequence annotation. There are five tables represented in the result pages: models, PDB structures, mutations, protein–protein interactions and virtual screening of ligands. The SARS-CoV-2 protein interaction with the human protein is annotated at the bottom of the page; the black arrows indicate human proteins annotated as drug targets.