Comparative Molecular Dynamics Reveals How LRRK2 Inhibitors Distinguish G2019S from Wild-Type

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has become a critical drug target in Parkinson's disease, with mutation-selective inhibitors offering promising potential for precision medicine. However, the structural similarity between G2019S and wild-type kinases presents a significant challenge in developing selective inhibitors. Although recent advances have led to inhibitors that selectively target G2019S or wild-type kinases, the selectivity mechanism of these inhibitors remains unclear. We employed molecular dynamics simulations to investigate and explore kinase-ligand interactions and identify the underlying mechanisms of selectivity. The results suggest that ligand binding drives the conformational changes, which is a key contributing factor to selectivity, rather than the strength of the ligand binding. The ligand-induced conformational changes lead to kinase destabilisation and inactivation. Additionally, key residues, such as Tyr2018 and Asp2017, were found to play pivotal roles in the selectivity. These insights underscore the importance of incorporating conformational dynamics into the design of future LRRK2 mutant-selective inhibitors.

Keywords: Conformational changes; G2019S/WT selectivity; Kinase-Ligand interaction; LRRK2 inhibitors; Molecular dynamics.

Fig. 1

The a sequence and b structure of the LRRK2 kinase domain with ATP bound (PDB ID: 7LHW). c Chemical structures of four G2019S/wild-type selective inhibitors

Fig. 2

The averaged root-mean standard deviation (RMSD) of three parallel trajectories for a protein in G2019S-selective systems and b protein in wild-type-selective systems

Fig. 3

Dynamic cross-correlation matrices (DCCM) for the crucial interval of a compound 53 in G2019S kinase; b compound 53 in wild-type kinase; c compound 52 in G2019S kinase; d compound 52 in wild-type kinase; e compound 30 in G2019S kinase; f compound 30 in wild-type kinase; g compound 31 in G2019S kinase; h compound 31 in wild-type kinase. Positive, non-relative, and negative values are represented by orange, yellow, green, blue, and purple, respectively. P–P: pocket–pocket; C–C: C-terminal–C-terminal

Fig. 4

Conformations of Asp2017-Glu1920 in representative conformations for a compound 53, b compound 52, c compound 30, and d compound 31. The G2019S-ligand complex was aligned with the wild-type-ligand complex, and the G2019S was painted colourful, and the wild-type was grey

Fig. 5

Binding conformations of the representative frames in G2019S-selective systems: a compound 53 in G2019S kinase; b compound 53 in wild-type kinase; c compound 52 in G2019S kinase; d compound 52 in wild-type kinase; e compound 30 in G2019S kinase; f compound 30 in wild-type kinase; g compound 31 in G2019S kinase; h compound 31 in wild-type kinase

Fig. 6

Per residue energy decomposition of the MM/GBSA calculation in the crucial interval for a Compound 53, b Compound 52, c Compound 30, and d Compound 31. ELA: Glu1948, Leu1949, and Ala1950. AVK: Ala1904, Val1905, and Lys1906. The free energy of significant residues is listed in Table S2

Fig. 7

Structural consequences of the Gly-2019-Ser mutation in a, b compound 52 and c, d compound 31 systems