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

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...

Examples

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...

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...

Examples

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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