Human-derived LRRK2 protein small-molecule inhibitor and application thereof

Abstract

The invention provides a small-molecule inhibitor taking human LRRK2 protein as a target spot and application of the small-molecule inhibitor, and belongs to the technical field of pharmacy. According to the invention, a three-dimensional structure of the kinase structural domain of LRRK2 is constructed by taking the kinase structural domain of LRRK2 as a target and using a homologous modeling method, an I-type inhibitor binding pocket of the three-dimensional structure is selected, a Glide program is used for molecular docking, virtual screening is carried out from more than 1,600,000 compounds to obtain a small-molecule inhibitor LY2019-006 targeting human LRRK2 protein; and a kinase activity inhibition experiment is carried out, the inhibition effect of the compound LY2019-006 on the LRRK2 kinase activity is verified, the molecular dynamics simulation research is performed, and the action mechanism of the compound LY2019-006 and the target protein is clarified on the molecular level. The found small molecules and pharmaceutical salts thereof can provide a basis for research and development of new 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 the lead compound can be further optimized, and the lead compound has a good application prospect.

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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