Leucine rich repeat kinase 2 (LRRK2) has been reported in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may provide new treatments for PD. In this study, novel LRRK2 inhibitors were identified by performing a docking-based virtual screening (VS). Due to the absence of a crystal structure of LRRK2, homology modeling was adopted to model human LRRK2 kinase domain that binds the inhibitor. Next, a docking-based virtual screening protocol was applied to identify LRRK2 small molecule inhibitors targeting the ATP binding pocket. A total of 28 compounds were selected and subjected to LRRK2 kinase inhibition assay. As a result, two small molecules with novel skeleton, compounds LY2019-005 and LY2019-006, were identified as potential LRRK2 kinase inhibitors with the IC50 of these two compounds against the wild-type and G2019S mutant LRRK2 kinase being 424.40 ± 1.31 nM, 378.80 ± 1.20 nM and 1526.00 ± 0.87 nM, 1165.00 ± 1.18 nM, respectively. Molecular dynamics (MD) simulation was carried out to reveal the binding mode of the newly identified compound LY2019-005 to the LRRK2 kinase domain. The binding modes indicate that the important hydrogen bond between hinge region (such as Ala1950) and inhibitor is crucial for the inhibition activity. In summary, our study provides a highly efficient way to discover LRRK2 inhibitors, and we find two highly efficient novel LRRK2 inhibitors, which could be helpful for the development of potential drugs targeting LRRK2 in PD therapy.
Keywords: LRRK2; docking-based virtual screening; homology modeling; inhibitor; molecular dynamics simulation.