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

A technology of protein drugs and medicinal salts, applied to medical preparations containing active ingredients, anti-inflammatory agents, organic active ingredients, etc., can solve problems such as insufficient specificity, certain toxicity, and inability to pass through the blood-brain barrier

Pending Publication Date: 2021-12-10
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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  • Human-derived LRRK2 protein small-molecule inhibitor and application thereof
  • Human-derived LRRK2 protein small-molecule inhibitor and application thereof
  • Human-derived LRRK2 protein small-molecule inhibitor and application thereof

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Embodiment 1

[0020] 1. High-throughput virtual screening method for small molecule compound LY2019-006

[0021] (1) Protein preparation

[0022] 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 200ns molecular dynamics simulation was carried out on the structure after homology modeling. Then through cluster analysis, re-docking method and Lagren diagram inspection, three stable representative protein structures were obtained for future virtual screening.

[0023] (2) Ligand preparation

[0024] The three-dimensiona...

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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 ...

Claims

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Application Information

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IPC IPC(8): C07D231/54A61K31/416A61P25/28A61P25/16A61P29/00A61P31/08
CPCC07D231/54A61K31/416A61P25/28A61P25/16A61P29/00A61P31/08
Inventor 刘焕香谈硕彦彭立增姚小军
Owner LANZHOU UNIVERSITY
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