Selective Stabilization of LRRK2 Kinase Conformations Reveals Distinct Modes of Action for Type I and II Inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for Parkinson’s disease, with type I inhibitors competing to the ATP pocket in closed-active conformation; in contrast, type II inhibitors occupy the open-inactive kinase, engaging both the ATP pocket and an adjacent allosteric site. This study employed molecular dynamics simulations to assess the conformational effects induced by the binding of MLi-2 (a type I inhibitor) and GZD-824 (a type II inhibitor). The results show that GZD-824 stabilizes the open, inactive conformation by controlling the rotation of DYG/S. Although MLi-2 does not stabilize the DYG/S motif in its closed position directly, it still maintains the kinase in a closed-active state by occupying the space where the DYG/S motif would need to move to adopt the open conformation. Additionally, MLi-2 preferentially binds to the G2019S variant, while GZD-824 favours the wild-type. These findings offer insights into LRRK2 conformational regulation, underscoring the broader significance of type-selective inhibitors in modulating kinase conformation.