Ligand‐centered assessment of SARS‐CoV‐2 drug target models in the Protein Data Bank

Abstract

A bright spot in the SARS‐CoV‐2 (CoV‐2) coronavirus pandemic has been the immediate mobilization of the biomedical community, working to develop treatments and vaccines for COVID‐19. Rational drug design against emerging threats depends on well‐established methodology, mainly utilizing X‐ray crystallography, to provide accurate structure models of the macromolecular drug targets and of their complexes with candidates for drug development. In the current crisis, the structural biological community has responded by presenting structure models of CoV‐2 proteins and depositing them in the Protein Data Bank (PDB), usually without time embargo and before publication. Since the structures from the first‐line research are produced in an accelerated mode, there is an elevated chance of mistakes and errors, with the ultimate risk of hindering, rather than speeding up, drug development. In the present work, we have used model‐validation metrics and examined the electron density maps for the deposited models of CoV‐2 proteins and a sample of related proteins available in the PDB as of April 1, 2020. We present these results with the aim of helping the biomedical community establish a better‐validated pool of data. The proteins are divided into groups according to their structure and function. In most cases, no major corrections were necessary. However, in several cases significant revisions in the functionally sensitive area of protein–inhibitor complexes or for bound ions justified correction, re‐refinement, and eventually reversioning in the PDB. The re‐refined coordinate files and a tool for facilitating model comparisons are available at https://covid-19.bioreproducibility.org. Database Validated models of CoV‐2 proteins are available in a dedicated, publicly accessible web service https://covid-19.bioreproducibility.org

Covid‐19.bioreproducibility.org: A web resource for SARS‐CoV‐2‐related structural models

“…Third, several scientists did not respond to our request to provide their data, despite the IUCr recommendation 43 and an appeal from the community to make diffraction data related to SARS-CoV-2 public (http://phenix-online.org/pipermail/phenixbb/2020-March/ 024556). However, in one case 6 our request resulted in the original authors re-depositing an optimized structure instead of depositing the diffraction data. All of the above facts show that the struggle for reproducibility of scientific results is an uphill battle, and suggest that leading scientific journals should do more 44,45 than run editorials about the need to improve the reproducibility of scientific results.…”

“…Some of these revisions were triggered by our resource. 6 Several structures have already been obsoleted and replaced with new deposits. In comparison, there were only seven coordinate replacements for all other structures deposited during that time (and among all the structures deposited in 2019, on average only less than 1 in 300 structures had a new version with coordinate replacement).…”

Anti-COVID Drugs: Repurposing Existing Drugs Or Search for New Complex entities, Strategies and Perspectives

“…Currently, many new proteins present in the SARS-CoV-2 are known every day. A review of such major protein molecular targets has been described in [ 44 ]. Each of them may, in the future, be a separate molecular target for molecules designed and proposed in this paper.…”

A review of COVID-19 biomarkers and drug targets: resources and tools

“…Protein Data Bank is a public resource collecting user deposited structures of all of the 29 COVID-19-related PDB structures [ 76 ]. Using used model-validation metrics Wlodawer et al [ 77 ] defined a refined version of COVID-19-related PDB structures present in Protein Data Bank and made them available at [ 78 ]. As of July 2020, this repository hosts 285 SARS-CoV-2 protein structures and 23 additional structures of other coronaviruses.…”