Structural Insights and Development of LRRK2 Inhibitors for Parkinson's Disease in the Last Decade

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

Keywords: G2019S mutation; LRRK2; Parkinson’s disease; kinase inhibitors; neurodegeneration.

Figure 1

Structure of LRRK2. (A) Domain organization of LRRK2. ARM—Armadillo repeats (pink), ANK—ankyrin repeats (yellow), LRR—leucine-rich repeat (green), ROC—Ras of complex (purple), COR—C terminal of Roc (cream), KIN—kinase domain (blue), WD40—WD repeat domain (grey). The mutation of the kinase domain is highlighted in black. The function of each domain is marked below the 2D diagram. (B) Surface representation of the cryo-EM structure of LRRK2. The color code was used the same as shown in the domain diagram. (C) Kinase domain of LRRK2. Active site region G-loop (purple), hinge (pink), DYG motif (cyan), αC-helix (blue), activation segment (orange) are highlighted. The position of mutation associated with PD is shown by stick representation. Figure created using Discovery Studio (DS) v19 (accessed on 10 February 2022) [55].

Figure 2

(A) Kinase domain ATP binding site. (B,C) Key molecular interactions involved in ATP interaction 3D and 2D representation. Important regions of active site G-loop (purple), hinge region (pink), DYG motif (cyan), and activation segment (orange), αC helix (blue), and the remaining part of the LRRK2 kinase domain is shown in grey-colored ribbon. ATP molecule is shown with a yellow stick. Figure created using Discovery Studio (DS) v19 (accessed on 12 February 2022) [69].

Figure 3

The LRRK2 activation cycle. In the cytosol, LRRK2 is monomeric and GTP-bound. This less active state forms a cytoplasmic complex with 14-3-3 proteins. LRRK2 is membrane-localized by activated Rab proteins. GTP hydrolysis occurs at membrane and results in LRRK2 dimerization. During the GTPase cycle, LRRK2 phosphorylates its substrates. Low LRRK2 affinity for GDP allows quick GDP release, rebinding of GTP, and monomerization of LRRK2 [100].

Figure 4

The 2D chemical structures of ATP competitive LRRK2 inhibitors.

Figure 5

(A) Schematic representation of the assembly of PROTAC machinery. (B,C) Representative PROTAC developed against LRRK2.