Proteases (also known as peptidases or proteinases) are a subgroup of hydrolase enzymes that catalyze proteolysis. There are two main subtypes of proteases: exoproteases which cleave peptide bonds at the terminus of polypeptide chains, and endoproteases which act internally by finding out a site of interaction. Proteases are taking part in a variety of physiological processes and represent potential drug targets for various diseases, ranging from cardiovascular disorders to cancer, as well as for combating many parasites and viruses.
Several techniques were implemented to create our target-focused library. A reference set of inhibitors of proteases from the ChEMBL database that contained substances with IC50 activity higher than 1 uM was prepared. Combination of docking method and similarity search against the reference compound set provided about 1,400 compounds available in-stock.
A number of customized dockings were carried out against separate targets. All simulations, including flexible and covalent docking and compound optimization process, were done with Sybyl-X software (Fig. 1).
Fig. 1. An example of the covalent docking (SYBYL-X) in Cathepsin B based on similarity search and preceding optimization step.
The list of targets used for the Protease TargetedLibrary preparation is represented below: