Exploring structural requirement, pharmacophore modeling, and de novo design of LRRK2 inhibitors using homology modeling approach

A mutation in the gene, encoding leucine rich repeat kinase 2 (LRRK2), is a genetic cause of Parkinson's disease (PD). LRRK2 is a dimeric multidomain protein, largely regulates guanosine triphosphate (GTP). G2019S and I2020T, the mutation encodes in the kinase domain of LRRK2 increase the GTPase activity, are the important regulators in pathogenesis of PD. To design potent LRRK2 inhibitors, pharmacophore modeling approach was employed with a wide chemical diversity of compound's database. The best hypothesis consists of hydrogen-bond acceptor and donor as well as hydrophobic aliphatic and ring aromatic features. The model was validated by the test and decoy sets followed by Fischer's randomization test. The validated model was used to screen the database of compounds, which were designed through de novo approach. Homology model of the kinase domain of LRRK2 was built initially using the crystal structure of Janus kinase 3. The designed molecules were further screened for ADMET properties, and ligand-receptor interaction of top hits was analyzed by molecular docking studies to explore potent LRRK2 inhibitors.