Small-molecule inhibitor for human-derived LRRK2 protein and application of small-molecule inhibitor

Abstract

The invention provides a small-molecule inhibitor with human-derived LRRK2 protein as a target spot and application of the small-molecule inhibitor, belonging to the technical field of pharmacy. According to the invention, a kinase structural domain of LRRK2 is taken as a target, a three-dimensional structure of the kinase structural domain of LRRK2 is constructed by using a homologous modeling method, an I-type inhibitor binding pocket of the three-dimensional structure is selected, molecular docking is carried out by using a Glide program, and the small-molecule inhibitor LY2019-005 targeting the human-derived LRRK2 protein is virtually screened out from more than 160,000 compounds; a kinase activity inhibition experiment is carried out, so the inhibition effect of the compound LY2019-005 on the activity of LRRK2 kinase is verified; and molecular dynamics simulation research is carried out, and the action mechanism of the compound LY2019-005 and target protein is clarified at a molecular level. The found small molecule and a pharmaceutical salt thereof can provide a basis for research and development of novel drugs for treating diseases related to LRRK2, such as Parkinson's disease, Alzheimer's disease, inflammatory bowel disease or Hansen's disease. The structure of a lead compound can be further optimized, and the lead compound has good application prospects.

Description

technical field [0001] The invention belongs to the technical field of biochemical pharmacy, and in particular relates to the use of a lead compound and a pharmaceutically acceptable salt thereof for inhibiting human LRRK2 kinase activity by targeting leucine-rich repeat kinase 2 (LRRK2) protein in the preparation of LRRK2-related disease medicines application. Background technique [0002] LRRK2 is a large protein with 2527 amino acids, belonging to the ROCO protein kinase family, including six domains including ARM, ANK, LRR, Roc-COR, Kinase and WD40. The Roc-COR domain has GTPase activity, and this domain binds guanine nucleotides and hydrolyzes GTP through the phosphate-binding motif (P loop) region (Biosa A et al. Human moleculargenetics.2013,22(6):1140- 56). The Kinase domain has ATP kinase activity. Kinase domains have been shown to phosphorylate a variety of cellular proteins in vitro, but the endogenous substrates remain unidentified. LRRK2 has been found to be ...

AI Technical Summary

Problems solved by technology

[0004]LRRK2 inhibitors can achieve the purpose of treating Parkinson's disease, Alzheimer's disease, inflammatory bowel disease and leprosy by inhibiting LRRK2 kinase activity. LRRK2 inhibitors are all ATP-competitive type I kinase inhibitors, most of which have problems such as insufficient specificity, inability to pass through the blood-brain barrier, and certain toxicity (Liu M et al. Biochemistry.2013,52(10):1725-36 ), there is still a need to discover improved LRRK2 inhibitors with novel backbones

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