Lead compound using human FKBP51 protein as target as well as screening method and application thereof

A lead compound, FK1 technology, applied in library screening, medical preparations containing active ingredients, chemical libraries, etc., can solve problems such as prostate cancer cell proliferation

Active Publication Date: 2016-09-28
LANZHOU UNIVERSITY
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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 using human FKBP51 protein as target as well as screening method and application thereof
  • Lead compound using human FKBP51 protein as target as well as screening method and application thereof
  • Lead compound using human FKBP51 protein as target as well as screening method and application thereof

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Embodiment 1

[0036] Chemical structures of lead compounds:

[0037]

[0038] 1. A high-throughput virtual screening method for lead compounds having a chemical structure of formula (I)

[0039] 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 using human FKBP51 protein as a target as well as a screening method and an application thereof, and belongs to the field of biochemical pharmacy technology. A FK1 domain of the FKBP51 protein is used as a receptor, a FK506 binding pocket of the receptor is selected, a Glide program is used for carrying out molecular docking, 150 small molecule compounds are obtained by virtual screening from more than 1.50 million compounds, and fluorescence quenching experiments are carried out for checking binding effects between the compounds and FK1; binding characteristics between the target protein and the compounds with high docking effects are researched, activities of the screened small molecule compounds against prostate cancer cells are checked by using two kinds of selected cells including LNCaP and DU145, and at the same time structural biology researches are carried out for compounds formed by FKBP51 and the small molecule lead compounds. The invention also establishes a cell model and a mice model of CRPC, effectiveness of the lead compounds on CRPC are evaluated, mechanisms and rules of action between the lead compounds and the target protein on molecular level are illustrated, and a foundation is provided for research and development of new drugs for treating common prostate cancer and CRPC.

Description

technical field [0001] The invention belongs to the technical field of biochemical pharmacy, and specifically relates to a lead compound with anti-prostate cancer activity targeting human FKBP51 protein, a screening method 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 androgen synt...

Claims

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Application Information

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IPC IPC(8): A61K31/5377C07D317/66A61P35/00C40B30/04C40B30/06C40B30/10
CPCA61K31/5377C07D317/66C40B30/04C40B30/06C40B30/10
Inventor 王志平何永兴武丹
Owner LANZHOU UNIVERSITY
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