Chemical IN04 Inhibits the Kinase Domain not the ROC Domain of LRRK1: Results from Homology Modeling and Molecular Docking
| Autor: | Weirong Xing, Zhenhang Chen, Li Fan |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Aging
kinase inhibitor Medicinal & Biomolecular Chemistry IN04 Protein Data Bank (RCSB PDB) Computational biology Protein Serine-Threonine Kinases Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ROC GTPase Article Domain (software engineering) leucine rich repeat kinase 1 Medicinal and Biomolecular Chemistry bone loss Drug Discovery Humans homology model Homology modeling Protein kinase A Phylogeny Aged biology Chemistry Active site molecular docking Pharmacology and Pharmaceutical Sciences Ligand (biochemistry) LRRK2 Molecular Docking Simulation Protein kinase domain 5.1 Pharmaceuticals biology.protein Osteoporosis Development of treatments and therapeutic interventions Protein Kinases |
| Zdroj: | Med Chem Medicinal chemistry (Shariqah (United Arab Emirates)), vol 17, iss 10 |
| ISSN: | 1573-4064 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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