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

A technology of protein drugs and medicinal salts, which is applied in the direction of anti-inflammatory agents, non-central analgesics, active ingredients of heterocyclic compounds, etc., and can solve problems such as insufficient specificity, inability to pass through the blood-brain barrier, and certain toxicity

Active Publication Date: 2021-05-28
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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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 wh

Method used

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

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Embodiment 1

[0021] 1. High-throughput virtual screening method for small molecule compound LY2019-005

[0022] (1) Protein preparation

[0023] Since the structure of the research target is unknown, it is necessary to use the method of homology modeling to construct the kinase domain model of LRRK2. According to the existing crystal structure (PDB code: 3dtc) of mixed-lineage kinases MLK1 (mixed-lineage kinases, MLK1) as a template (identities 31%; postive 51%), using The Prime module of the software constructs the LRRK2 kinase domain (the amino acid sequence is 1879-2138). In order to obtain a more stable and reasonable structure of the kinase domain of LRRK2, a 200 ns molecular dynamics simulation was performed on the homology modeled structure. Then through cluster analysis, re-docking method and Lagren diagram inspection, three stable representative protein structures were obtained for future virtual screening.

[0024] (2) Ligand preparation

[0025] The three-dimensional struct...

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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 ...

Claims

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Application Information

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IPC IPC(8): A61K31/53A61P25/16A61P25/28A61P29/00A61P31/04
CPCA61K31/53A61P25/16A61P25/28A61P29/00A61P31/04
Inventor 刘焕香谈硕彦彭立增姚小军
Owner LANZHOU UNIVERSITY
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