Method for screening compound with targeted action on inactive conformation of protein kinase

A technology of inactive conformation and protein kinase, which is applied in the field of protein structure prediction and virtual screening of drug molecules, and can solve problems such as long-term treatment

Inactive Publication Date: 2011-08-17
FUDAN UNIV
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Problems solved by technology

[0009]Currently, drug-sensitive tuberculosis is curable but requires a long course of treatment and the use of multiple drugs
Not only that, for Mycobacterium tuberculosis (Mycobacterium tuberculosis), more and more drug-resistant strains have emerged, and how to effectively control the infection of tuberculosis is also facing severe challenges

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  • Method for screening compound with targeted action on inactive conformation of protein kinase
  • Method for screening compound with targeted action on inactive conformation of protein kinase
  • Method for screening compound with targeted action on inactive conformation of protein kinase

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Embodiment Construction

[0079] The method of the present invention is applied to the calculation process of Mycobacterium tuberculosis protein kinase PknB:

[0080] The first step, the construction of the kinase inactive conformation ensemble:

[0081] a) Download the PDB file 1O6Y of PknB protein kinase, remove the heteroatoms in it, and perform preliminary optimization after filling;

[0082] b) As mentioned above, extract the coordinates of 4 atoms to calculate the sum of the required distances, and the value is 29.64 ?, indicating that the N-lobe of 1O6Y in front of the active chain segment needs to be rotated outward by 15 degrees;

[0083] c) Obtain the desired initial conformation after rotation, and calculate the remodeling of the active segment after setting each parameter file;

[0084] d) Among the 200 prediction models obtained, 163 were judged as DFG-out conformation by vector method;

[0085] e) These conformations are tested for the space size of the active site, and 8 conformation...

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Abstract

The invention belongs to the technical field of protein structure prediction and drug molecule virtual screening, specifically to a method for screening a compound with targeted action on an inactive conformation of a protein kinase. The method provided by the invention comprises a prediction method for the conformation of an active chain section of the protein kinase, wherein a corresponding DFG-out inactive conformation is generated from the DFG-in active conformation of the protein kinase; the method also comprises a selection method of a combined conformation after implementing butt joint of a II type inhibitor, and the selection method is used for selecting small molecules in conformation prediction and virtual screening. The method for screening a compound with targeted action on an inactive conformation of a protein kinase is already calculated and verified in the protein kinases of seven types of known inactive conformations, wherein the success rate is close to 96%. The method provided by the invention is already applied to the prediction of inactive conformation of PknB protein kinase of tubercle bacillus and the virtual screening of a possible II type inhibitor of PknB, and the bacteriostasis of two kinds of small molecules are already found according to bacteriostatic experiments.

Description

technical field [0001] The invention belongs to the technical field of protein structure prediction and drug molecule virtual screening, and specifically relates to a method for predicting and screening the inactive conformation of protein kinase, and a method for predicting and virtual screening the docking conformation of protein kinase II inhibitors. Background technique [0002] With the completion of human genome sequencing, it was found that about 518 different genes in the genome encode various kinases, accounting for about 2% of the total number of genes. This huge family of protein kinases regulates almost all aspects of cell activities, including signal transduction, DNA transcription, cell metabolism, and cell cycle operation, and then controls cell differentiation and apoptosis. Therefore, the activation and inactivation of kinases are very important. Once abnormal, it will lead to the occurrence of various diseases, including cancer, central nervous system disor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G06F19/10
Inventor 黄强徐旻张雪莲王洪海万波
Owner FUDAN UNIV
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