Genetic Variability of the SARS-CoV-2 Pocketome.

In the absence of effective treatment, COVID-19 is likely to remain a global disease burden. Compounding this threat is the near certainty that novel coronaviruses with pandemic potential will emerge in years to come. Pan-coronavirus drugs-agents active against both SARS-CoV-2 and other coronaviruses-would address both threats. A strategy to develop such broad-spectrum inhibitors is to pharmacologically target binding sites on SARS-CoV-2 proteins that are highly conserved in other known coronaviruses, the assumption being that any selective pressure to keep a site conserved across past viruses will apply to future ones. Here we systematically mapped druggable binding pockets on the experimental structure of 15 SARS-CoV-2 proteins and analyzed their variation across 27 α- and ß-coronaviruses and across thousands of SARS-CoV-2 samples from COVID-19 patients. We find that the two most conserved druggable sites are a pocket overlapping the RNA binding site of the helicase nsp13 and the catalytic site of the RNA-dependent RNA polymerase nsp12, both components of the viral replication-transcription complex. We present the data on a public web portal (https://www.thesgc.org/SARSCoV2_pocketome/), where users can interactively navigate individual protein structures and view the genetic variability of drug-binding pockets in 3D.

Structure-based view of the druggable genome.

International efforts are underway to develop chemical probes for specific protein families, and a 'Target 2035' call to expand these efforts towards a comprehensive chemical coverage of the druggable human genome was recently announced. But what is the druggable genome? Here, we systematically review structures of proteins bound to drug-like ligands available from the Protein Data Bank (PDB) and use ligand desolvation upon binding as a druggability metric to draw a landscape of the human druggable genome. The vast majority of druggable protein families, including some highly populated and disease-associated families, are almost orphan of small-molecule ligands. We propose a list of 46 druggable domains representing 3440 human proteins that could be the focus of large chemical probe discovery efforts.