Discovery of LRRK2 inhibitors using sequential in silico joint pharmacophore space (JPS) and ensemble docking

Abstract

Joint pharmacophore space (JPS), ensemble docking and sequential JPS-ensemble docking were used to select three panels of compounds (10 per panel) for evaluation as LRRK2 inhibitors. These computational methods identified four LRRK2 inhibitors with IC50 values <12μM. The sequential JPS-ensemble docking predicted the majority of active hits. One of the inhibitors (Z-8205) identified using this method was also found to inhibit the G2019S mutant of LRRK2 25-fold better than wild-type enzyme. This bias for the G2019S mutant is proposed to arise from an interaction with S2019 in this form of the enzyme. In addition, Z-8205 was found to only inhibit one other kinase when profiled against a panel of 97 kinases at 10μM.

Keywords: Ensemble docking; In silico; Inhibitor; Joint pharmacophore space; LRRK2.