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Construction method and application of three-dimensional quantitative structure-activity relationship model of bcl-2 protein inhibitor

A protein inhibitor and three-dimensional quantitative technology, applied in the field of bioinformatics, can solve problems such as side effects, lack of targeting, and difficulty in penetration, and achieve the effect of improving screening efficiency and reducing costs

Inactive Publication Date: 2011-11-30
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, studies have found that while antisense oligonucleotide molecules inhibit the expression of Bcl-2 protein, they are prone to side effects due to lack of targeting
At the same time, the BH3 domain mimic peptide has poor affinity, is difficult to penetrate into cells, and has poor selectivity for tumor cells

Method used

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  • Construction method and application of three-dimensional quantitative structure-activity relationship model of bcl-2 protein inhibitor
  • Construction method and application of three-dimensional quantitative structure-activity relationship model of bcl-2 protein inhibitor
  • Construction method and application of three-dimensional quantitative structure-activity relationship model of bcl-2 protein inhibitor

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Embodiment 1

[0034] The present invention involves the use of known small molecule inhibitors (see Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL, Brucko, M., et al. J. Med. Chem., 2007, 50, 641) A method for constructing a three-dimensional quantitative structure-activity relationship model for Bcl-2 protein inhibitors.

[0035] The method includes the following steps:

[0036] (1) According to a total of 31 known small-molecule inhibitors involved in the report, their biological activities are determined by the binding constant K i express. with the binding constant K i The negative logarithm pK of i (pK i =log K i ), this class of inhibitors is divided into three categories, where pK i i i >8, representing weak binding ability, medium binding ability, and strong binding ability to Bcl-2 protein, respectively. Twenty-six known small-molecule inhibitors were selected from the three categories as the training set to build the prediction model, and the remaining 5 kno...

Embodiment 2

[0043] A method for constructing a three-dimensional quantitative structure-activity relationship model of Bcl-2 protein inhibitors described in Example 1 was used to analyze the activity of different Bcl-2 protein inhibitors in the mother nucleus.

[0044] 1. WL-276 is a known small molecule inhibitor recently reported, it can effectively inhibit Bcl-2 protein, and its core structure is 2-thio-4-thiazolidinone, which is established in Example 1. The known small molecule inhibitors used in the model have different core structures;

[0045] 2. Accelrys Draw 4.0 (Accelrys Inc.) was used to construct the two-dimensional structure of WL-276, and Concord (SYBYL7.3, Tripos Inc.) was used to convert the two-dimensional structure into three-dimensional structure;

[0046] 3. Because the structure of WL-276 is quite different from the positive compounds with existing three-dimensional structures, in order to obtain the three-dimensional structure of WL-276 that is closer to the real va...

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Abstract

The invention relates to a method for constructing a three-dimensional quantitative structure activity relationship model of a B-cell lymphoma-2 (Bcl-2) protein inhibitor and application of the method and belongs to the technical field of biological information. The method comprises the following steps of: according to the known small molecule inhibitor, establishing the three-dimensional quantitative structure activity relationship model of the Bcl-2 protein inhibitor by using a three-dimensional quantitative structure activity relationship technology; and further improving the accuracy of the model by using technologies for analyzing molecular similarity, optimizing molecular conformation, optimizing parameters and the like. By the invention, the Bcl-2 protein binding constants of an active unknown compound can be quickly predicted, and clues of the active compound are acquired within short time. Compared with the conventional high-throughput screening technology, the invention has the advantages of greatly improving screening efficiency and reducing cost.

Description

technical field [0001] The invention relates to a construction method and application of a three-dimensional quantitative structure-activity relationship model of a Bcl-2 protein inhibitor, in particular to the establishment of a three-dimensional quantitative structure-activity relationship model of an inhibitor taking Bcl-2 protein as a target and the use of the model for rapid drug development Screening belongs to the field of biological information technology. Background technique [0002] Malignant tumor (also known as cancer) is a major disease that threatens human health at present, and its morbidity and mortality have always been high. According to the World Health Organization, more than 7 million people worldwide die of cancer every year. In order to defeat cancer, all countries have invested a lot of manpower and material resources in research. At present, the clinical treatment of cancer mainly relies on cytotoxic drugs, which have the disadvantages of large to...

Claims

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Application Information

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IPC IPC(8): G06F19/10
Inventor 侯旭奔方浩
Owner SHANDONG UNIV
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