The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Abstract

SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor-antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

Keywords: SARS-CoV-2; mutation/variation; protein 3D structures; structural bioinformatics; structure prediction; therapeutics.

Figure 1

Structural information of SARS-CoV-2 from single proteins to organelles. Structural information on SARS-CoV-2 range from high-resolution single protein structures in PDB to lower resolution EM maps in EMDB and organelles and cells in EMPIAR.

Figure 2

Aggregated overview of structural data for the SARS-CoV-2 3C-like proteinase. Collating all the available structural information on the protein level can yield valuable insights. This is demonstrated in the aggregated view of SARS-CoV-2 3C-like proteinase at PDBe-KB (https://pdbekb.org/proteins/PRO_0000449623) that collates data from over 160 PDB entries (panel A). The residue-level interactions between the protein and over 140 distinct small molecules can be visualized both on a 2D sequence feature viewer (panel B) and using a molecular graphics viewer (panel C), superposing every small molecule and highlighting residues that are consistently involved in binding to various small molecules.

Figure 3

Screenshots from the SWISS-MODEL SARS-CoV-2 web resource (A) model of the viral NSP14 (B) model of the host interactor Procollagen galactosyltransferase. Shown along with the models are the quality estimates, template alignment, etc.

Figure 4

Screenshots from Aquaria web resource (A) Homepage showing all the SARS-CoV-2 proteins (B) RNA polymerase complex colored using UniProt chain features.

Figure 5

An account of structure-based studies on spike (S) protein of SARS-CoV-2. Some of the applications using spike protein in SARS-CoV-2 are illustrated, as follows. (I) The crystal structure of the SARS-CoV-2 receptor-binding domain (RBD; shown in purple) in complex with human ACE2 receptor (gray) is depicted using Chimera [PDB ID: 6M0J]. The direct contact residues (shown in red while residues in secondary shell are shown in blue) as well as key hotspot positions 31 and 353 (encircled in orange) are studied by various groups [6, 7]. (II) The impact of mutations at hotspot residue 353, on the stability of the RBD-ACE2 complex in various hosts (A. human, B. horseshoe bat, C. cat and dog) are illustrated (Source of images (I) and (II) and more details in Lam et al. [124]). (III) The crystal structure of RBD (purple) in complex with human antibody CR3022 (heavy chain: blue, light chain: cyan) is resolved (PDB ID: 6W41). (IV) Structure-based design of prefusion conformation of spike: design of vaccine candidate namely HexaPro: the high resolution cryo-EM structure is solved by Hsieh et al. [18]; Source of Image: Hsieh et al. [18].

Figure 6

Antiviral drugs repurposed against COVID-19, for which 3D structures of the ligand-protein complex were determined experimentally. Both approved drugs against chronic hepatitis C, boceprevir and telaprevir, inhibit SARS-CoV-2 main protease (3CLpro) and are clinically evaluated in different association. Veterinary molecule against feline CoV infection, GC376, is a prodrug generating an irreversible nanomolar 3CLpro inhibitor and will probably enter clinical phase. Remdesivir, a late development drug against Ebola virus, is a SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp) strong inhibitor and received emergency use authorization for COVID-19 in Europe and USA. Favipiravir, used in influenza infection, is a RdRp inhibitor investigated against SARS-CoV-2 infection.

Figure 7

SARS-CoV-2 Main protease (3CLpro): earliest, advanced structure-based drug discovery routes (pdb entry, resolution, release date). The proteins are displayed in beige cartoon and the ligands in colored ball-and-sticks. (A) the first crystal of 3CLpro enabled the discovery of disulfiram and carmofur as potential drugs to repurpose through structure-based virtual and high-throughput screenings [10] as well as the design of peptidomimetic covalent ligands [159]; (B) an apo crystal was subject to structure-based design for covalent ligands [148] and recently brought rational for repurposing a non-covalent small molecule initially developed as a kinase inhibitor; (C) The XChem initiative started with the resolution of an apo structure allowing soaking experiments that led to more than 80 cocrystals with covalent and non-covalent fragments, most are located in the active site.