A kind of screening method of bcr-abl protein kinase inhibitor

A protein kinase inhibitor, bcr-abl technology, applied in the field of drug screening, to achieve non-toxic, good inhibitory effect on normal cells, and the effect of inhibiting CML variant tumors

Active Publication Date: 2022-02-22
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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AI Technical Summary

Problems solved by technology

Calculating the kinetic residence time of a large number of protein-small molecule complexes using molecular dynamics simulations is still very challenging theoretically

Method used

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  • A kind of screening method of bcr-abl protein kinase inhibitor
  • A kind of screening method of bcr-abl protein kinase inhibitor
  • A kind of screening method of bcr-abl protein kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0069] 1) Similarity screening

[0070] About 40,000,000 small molecules in the PubChem database were initially screened by using Tanimoto similarity search. Small molecules in the library with a structural similarity greater than 90% of the Tanimoto coefficient to any of imatinib, nilotinib, dasatinib and ponatinib were retained for the next step of molecular docking. Through this step of screening, a group of small molecule compounds with a relatively small number but very similar structures to drug molecules were obtained. The results are shown in Table 1. In addition, the diversity small molecule group ( diversity set) as a comparison group.

[0071] Table 1. The number of small molecule compounds with high similarity to existing drug molecules in the pubchem database

[0072]

[0073] 2) Docking and energy calculation

[0074] The small molecules obtained above were docked with four targets (activated wild type (PDB ID 2GQG), activated T315I mutant (PDB...

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Abstract

The present invention provides a method for screening Bcr-Abl protein kinase inhibitors. Firstly, small molecules with high similarity to known Bcr-Abl protein kinase inhibitors obtained through Tanimoto similarity search are docked with docking targets, and then used The scoring function SPA scores the intermolecular interaction of the protein-small molecule docking conformation to obtain the affinity value E; and combines the obtained affinity value E with the thermodynamic specificity and kinetic specificity formula to calculate the The thermodynamic specificity ISR value and kinetic specificity RT value of molecule and docking target, finally obtain the Bcr-Abl protein kinase inhibitor with formula (I) structure; The result shows that the inhibitor that screening method obtains has very good to CML cell The inhibitory effect is non-toxic to normal cells in a large concentration range, and has the effect of inhibiting CML variant tumors comparable to ponatinib.

Description

technical field [0001] The invention relates to the field of drug screening, in particular to a screening method for Bcr-Abl protein kinase inhibitors. Background technique [0002] Bcr-Abl tyrosine kinase is a kind of protein kinase, which is expressed by bcr-abl oncogene. The Bcr-Abl oncogene is formed by rearrangement of the abelson (abl) gene on chromosome 9 and the break point cluster (bcr) gene on chromosome 22. The persistent activity of Bcr-Abl tyrosine kinase is the cause of chronic myeloid leukemia (CML). Enhanced kinase activity is responsible for intracellular phosphorylation and activation of various signaling molecules, which accelerate cell proliferation and inhibit cell apoptosis. Therefore, inhibition of Bcr-Abl tyrosine kinase activity is an effective approach for targeted therapy of CML. [0003] Imatinib was the first drug approved by the FDA for the treatment of CML in 2001, and it was also the first kinase inhibitor. Bcr-Abl tyrosine kinase is a typ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G16B15/00G16C20/50
CPCG16B15/00G16C20/50
Inventor 晏致强汪劲夏艳赵银苹
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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