Covalent drugs are a class of therapeutics, which form a covalent bond with the target protein. Covalent interaction with the target protein has the benefit of prolonged duration of the biological effect and potential for improved selectivity. In order to facilitate rapid structure-based discovery of new and diverse covalent drugs, there is need for fast and effective structure-based virtual screening tools. Here, we present a fully automated covalent docking approach suitable for large-scale virtual screening, which we referred to as CovDock-VS. We applied this method to four targets (HCV NS3 protease, Cathepsin K, EGFR, and XPO1) with known crystal structures and known covalent inhibitors. Known actives and target-specific sets of decoys were docked to selected X-ray structures and poses were filtered based on non-covalent protein-ligand interactions known to be important for activity. CovDock-VS approach could handle multiple chemical reactions within the same library, only requiring a generic SMARTS-based predefinition of the reaction and was able to differentiate actives from decoys without significantly deteriorating the accuracy of the predicted poses for covalent protein-ligand complexes.

Structure-based virtual screening approach for discovery of covalently bound ligands

248th National Meeting (2014)

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