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Lead compound for targeted human FKBP51 protein and screening method and application thereof

A lead compound, FK1 technology, applied in compound screening, biochemical equipment and methods, organic chemistry, etc., can solve problems such as prostate cancer cell proliferation

Inactive Publication Date: 2016-08-31
LANZHOU UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Two research groups have reported that in prostate cancer cells, FKBP51 promotes the activity of AR and increases the ability of AR to bind to androgen, thereby upregulating the expression of downstream genes regulated by AR, leading to the proliferation of prostate cancer cells.

Method used

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  • Lead compound for targeted human FKBP51 protein and screening method and application thereof
  • Lead compound for targeted human FKBP51 protein and screening method and application thereof
  • Lead compound for targeted human FKBP51 protein and screening method and application thereof

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Experimental program
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Embodiment 1

[0037] Chemical structures of lead compounds:

[0038]

[0039] 1. A high-throughput virtual screening method for lead compounds having a chemical structure of formula (I)

[0040] Using the Schrödinger program package, download the crystal structure of the FK1 domain of FKBP51 from the protein structure database PDB (PDB code: 305R), use Prime, QSite, Liasion and MacroModel and other programs to optimize the structure, add charges and hydrogen atoms, and select its The FK506 binding pocket uses the molecular docking program Glide to perform high-throughput virtual screening from more than 1.5 million compounds provided by Chemdiv. The screening is performed on a 4-core CPU server, and about 100,000 compounds can be screened every day. QikProp calculates the physicochemical properties of the screened small molecule lead compounds, such as lipid-water partition coefficient QPlogPo / w, etc., and screens out the top 150 small molecule lead compounds with the best docking-score ...

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Abstract

The invention provides a lead compound for a targeted human FKBP51 protein and a screening method and application thereof, belonging to the technical field of biochemical pharmacy. According to the lead compound and the screening method and application thereof, an FK1 structural domain of FKBP51 is used as a receptor; FK506 of the FKBP51 is selected to be combined with a sack; molecular docking is performed by using a Glide program; 150 small molecular compounds are obtained by virtual screening from more than 1.5 million of compounds and are used for fluorescence quenching experiments; according to the experiments, a combination action of the compounds and the FK1 is verified, and the binding property of a target protein and compounds with a strong docking effect is researched; two kinds of cells LNCaP and DU145 are selected to verify the cell viability of screened small molecular compounds resisting prostate cancer; meanwhile, the structural biology research on a compound formed by the FKBP51 and small molecular lead compounds is performed. According to the lead compound provided by the invention, a cell model and a mouse model of CRPC (Castration Resistant Prostate Cancer) are established, the effectiveness of the lead compound to the CRPC is evaluated, and an action mechanism and a rule of the lead compound and the target protein are explained at the molecular level; a foundation is provided for researching and developing new drugs for treating common prostate cancer and the CRPC.

Description

technical field [0001] The invention belongs to the technical field of biochemical pharmacy, and in particular relates to a lead compound targeting human FKBP51 protein with anti-prostate cancer activity, a screening method thereof and an application in preparation of castration-resistant prostate cancer drugs. Background technique [0002] Androgen receptor (AR) is considered to play a key role in the occurrence, development and metastasis of prostate cancer. Therefore, androgen deprivation therapy (androgen deprivation therapy) has become the most common and effective method for the treatment of advanced prostate cancer. But within two to three years of treatment, most advanced prostate cancers develop castration-resistant prostate cancer (CRPC). The current lack of effective treatment for CRPC has become the most difficult problem in the treatment of prostate cancer. In the environment of androgen withdrawal, there are many ways of AR reactivation, mainly including andr...

Claims

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Application Information

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IPC IPC(8): A61K31/4015A61P35/00A61P13/08C07D207/416C12Q1/02
CPCA61K31/4015C07D207/416G01N33/5011G01N2500/10
Inventor 王志平何永兴武丹
Owner LANZHOU UNIVERSITY
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