Molecular Modeling Study on the Interaction Mechanism between the LRRK2 G2019S Mutant and Type I Inhibitors by Integrating Molecular Dynamics Simulation, Binding Free Energy Calculations, and Pharmacophore Modeling

Leucine-rich repeat kinase 2 (LRRK2) has been reported in the pathogenesis of Parkinson's disease (PD). G2019S mutant is the most common pathogenic mutation in LRRK2-related PD patients. Inhibition of LRRK2 kinase activity is proposed to be a new therapeutic approach for PD treatment. Therefore, understanding the molecular basis of the interaction between LRRK2 and its inhibitors will be valuable for the discovery and design of LRRK2 inhibitors. However, the structure of human LRRK2 in complex with the inhibitor has not been determined, and the inhibitory mechanism underlying LRRK2 still needs to be further investigated. In this study, molecular dynamics (MD) simulation combined with the molecular mechanics generalized born surface area (MM-GBSA) binding free energy calculation and pharmacophore modeling methods was employed to explore the critical residues in LRRK2 for binding of inhibitors and to investigate the general structural features of the inhibitors with diverse scaffolds. The results from MD simulations suggest that the hinge region residues Glu1948 and Ala1950 play a significant role in maintaining the intermolecular hydrogen bond interaction with the G2019S LRRK2 protein and inhibitor. The strong hinge hydrogen bond with an occupancy rate of more than 95% represents the high activity of LRRK2 inhibitors, and the hydrogen bond interaction with the kinase catalytic loop region could compromise selectivity. Further pharmacophore modeling reveals that the high activity LRRK2 inhibitor should have one aromatic ring, one hydrogen bond acceptor, and one hydrogen bond donor. Hence, the obtained results can provide valuable information to understand the interactions of LRRK2 inhibitors at the atomic level that will be helpful in designing potent inhibitors of LRRK2.