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NTR1 micromolecular antagonist

A technology of small molecules and antagonists, applied in the field of the structure of NTR1 small molecule inhibitors, can solve the problems of dysregulation of intracellular signal transduction pathways, disordered physiological responses, abnormal physiological phenomena, etc., and achieve the effect of good drug application prospects.

Inactive Publication Date: 2015-07-01
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Excessive activation or inhibition of GPCR may lead to dysregulation of intracellular signal transduction pathways, resulting in disordered physiological responses and abnormal physiological phenomena

Method used

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  • NTR1 micromolecular antagonist
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  • NTR1 micromolecular antagonist

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Example 1, Virtual Screening and Cell Viability Testing of NTR1 Small Molecule Inhibitors

[0021] One, the method for virtual screening of the present invention comprises following 4 steps:

[0022] Step 1: Construction of NTR1 Small Molecule Database

[0023] Integrate multiple commercial small molecule databases (including ZINC, SPECS, J&K Screening Library, InterBioScreening, Timtec, Msdiscove, Iris-biotech, TCM Database, Ambinter Natural Products, AnalytiCon Discovery NP, Princeton NP, Molecular Diversity Preservation International, PUBCHEM), with The Pipeline pilot software removes repetitive molecules and molecules with similar structures, and selects compounds with good absorption and low toxicity according to the calculated ADMET properties of the molecules for Clustering, obtaining a database of 1 million small molecules. The Glide module in Schrodinger was used to dock these small molecules with NTR1 with SP precision, and the top 10,000 small molecules scor...

Embodiment 2

[0039] Example 2. Structural modification based on the mode of action between the small molecule and the receptor NTR1.

[0040] Firstly, open the three-dimensional crystal structure of NTR1 protein in Discovery Studio3.5, the structure comes from PDB (Protein Data Bank), and the PDB number is 4GRV. Hydrogenate it, remove water, delete the inserted T4 lysozyme structure, use the Prepare Protein module to prepare the protein, and use Define Site to find the active site according to the NT in the ligand. Small molecules were prepared using the Prepare Ligands module. After the preparation is complete, use the Libdock method of the Dock Ligands module for docking, and the docking results are as follows figure 1 shown. According to the docking results, compound 1 forms hydrogen bonds with the key amino acids Arg327 and Tyr347 of the receptor reported in the literature, and the bond lengths of the hydrogen bonds are ( figure 1 ), the hydrogen bonding is very important for the ...

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Abstract

The invention provides an NTR1 micromolecular antagonist and relates to the fields of drug design science and pharmacology. Compounds having a general formula I as shown in the specification are provided by virtue of virtual screening, cell activity testing and structural modification based on a receptor, wherein R1 represents methyl, halogenated methyl, methoxyl, hydroxyl, hydroxymethyl, ethyl or a halogen atom; R2 represents hydroxyl, methyl, methoxyl, ethyl, ethoxyl, a halogen atom, a halogenated methyl or a halogenated ethyl; X represents sulfur, oxygen, nitrogen or carbon. The compounds have inhibition activity on NTR1 and have important use in preparing drugs for treating NTR1 protein related diseases.

Description

technical field [0001] The present invention relates to the fields of drug design and pharmacology, in particular, relates to the structure of a series of NTR1 small molecule inhibitors obtained through virtual screening, cell activity testing, and receptor-based structural modification. Background technique [0002] G Protein-Coupled Receptor (GPCR) has seven transmembrane structures, is widely distributed in the body, and participates in the response activities to various signaling molecules. GPCR and its signal transduction system are usually in a dynamic balance, and according to the changes of various physiological factors, the regulation of downstream signaling pathways is initiated to maintain the stability of the intracellular environment; under pathological conditions, cells also receive external signals through GPCR to affect cell life. Activities are adjusted. Especially in malignant tumor cells, GPCR regulates the occurrence, growth, invasion and metastasis of t...

Claims

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Application Information

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IPC IPC(8): C07D417/12A61K31/427A61P35/00A61P35/04A61P25/16A61P25/18
Inventor 徐峰张果李晓丹王坤田园诗
Owner NANKAI UNIV
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