Development of Energy-based Pharmacophore Model and Stepwise Virtual Screening of LRRK2 Inhibitors Through Molecular Dynamics and Mechanics

Out of many idiopathic causes, mutation in some genes is linked to Parkinson’s disease (PD). Recent studies showed pathogenic mutation in the kinase domain of the leucine rich repeat kinase (LRRK2) leads to PD, and increasingly gaining attention as a promising therapeutic target. Some of the reported LRRK2 inhibitors have shown undesirable drug properties, primarily the inability to cross the blood-brain barrier. The energy based approach of pharmacophore modeling, which blends ligand- and structure-based methods, has been used to identify new hits of LRRK2 inhibitors. The successful LRRK2 inhibitors in pre-clinical trials, such as GSK2578215A, HG-10-102-01 and GNE-7915 showing high brain penetrability, were selected for developing pharmacophore models. Throughput virtual screening combined with ADMET and molecular docking of molecular databases led to identification of potential LRRK2 inhibitors, substantiated through molecular dynamics and MM-GBSA analyses.