Title:Chemical IN04 Inhibits the Kinase Domain not the ROC Domain of LRRK1: Results from Homology Modeling and Molecular Docking
Volume: 17
Issue: 10
Author(s): Zhenhang Chen, Weirong Xing*Li Fan*
Affiliation:
- Department of Medicine, Loma Linda University, Loma Linda, CA,United States
- Department of Biochemistry, University of California Riverside, Riverside, CA,United States
Keywords:
bone loss, leucine rich repeat kinase 1, IN04, homology model, molecular docking, kinase inhibitor, ROC GTPase.
Abstract:
Background: Bone loss is the most common reason for broken bones among the elderly.
An ideal agent for the treatment of bone loss should have both osteoclast inhibitory and osteoblast
stimulatory functions. Leucine-rich repeat kinase 1 (LRRK1) is a novel target for alternative antiresorptive
drugs to treat osteoporosis and osteoporotic fractures. Recently a chemical IN04, Methyl
3-[({([5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-thio}-acetyl)-amino]-benzoate, has been identified
as a potential LRRK1 inhibitor.
Objective: The aim of this work is to investigate how the chemical IN04 interacts with LRRK1 and
inhibits its activity.
Methods: A structural model of the LRRK1 kinase domain was constructed with SWISS-MODEL.
The human protein kinase ROCO4 (PDB ID: 4YZN) was chosen as the template based on sequence
homology, structural and phylogenetic analysis. In addition, a homology model of the LRRK1 ROC
domain was also prepared based on the LRRK2 ROC domain structure (PDB ID: 2ZEJ). The interactions
of IN04 with the active sites in the LRRK1 kinase domain and ROC domain were investigated
by SwissDock.
Results: IN04 was docked into the active site of the LRRK1 kinase domain with similar interactions
as ATP comparable to the ligand bound to homologous kinases. Many rational binding modes of
IN04 to LRRK1 kinase domain were investigated and the most likely binding pose containing multiple
hydrogen bonds and a salt bridge was discovered. However, IN04 cannot fit into the GDP-binding
site of the ROC domain.
Conclusion: Chemical IN04 inhibits LRRK1 by binding to the active site of the kinase domain but
not the ROC domain.
