SCARdock: A Web Server and Manually Curated Resource for Discovering Covalent Ligands.

Abstract

Covalent drugs have been intentionally discarded historically due to the concern of off-target side effects, but the past decade has seen a fast resurgence of the discovery of covalent drugs. Compared to noncovalent ligands, covalent ligands might have better biochemical efficiency, lower patient burden, less dosing frequency, less drug resistance, and improved target specificity. Previously, we proposed the steric-clashes alleviating receptor (SCAR) strategy for screening and repurposing covalent inhibitors. To help the discovery of covalent ligands targeting protein targets, we have developed a web server dedicated to providing the SCARdock protocol to general users. Along with this server, we presented three high-quality data sets for the discovery of covalent ligands: a manually curated data set containing 954 high-quality complex structures of covalent ligands and proteins, a manually curated data set of 68 experimentally confirmed covalent warheads targeting 11 different residues, and a prefiltered, classified, and ready-to-use data set of 690,018 entries of purchasable virtual compounds containing these experimentally verified warheads. The SCARdock server and the accompanied data sets would be of great value to the discovery of covalent ligands and are available freely at http://www.liugroup.site/scardock/ or https://scardock.com.