Computer screening method for small molecular covalent inhibitors and application of method to screening of S-adenosylmethionine decarboxylase covalent inhibitors

A technology of covalent inhibition of adenosylmethionine decarboxylase, which is applied in the field of biomedicine, can solve problems such as tail deviation, and achieve the effects of accelerated screening, simple operation, and good predictive effect

Active Publication Date: 2017-02-15
CHINA THREE GORGES UNIV
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  • Abstract
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Problems solved by technology

[0004] Based on this, the present invention provides a computer-aided screening method for small-molecule covalent inhibitors, which ca

Method used

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  • Computer screening method for small molecular covalent inhibitors and application of method to screening of S-adenosylmethionine decarboxylase covalent inhibitors
  • Computer screening method for small molecular covalent inhibitors and application of method to screening of S-adenosylmethionine decarboxylase covalent inhibitors
  • Computer screening method for small molecular covalent inhibitors and application of method to screening of S-adenosylmethionine decarboxylase covalent inhibitors

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Embodiment 1

[0047] 1) Delete the pyruvyl 68 (Pyr) residue in the crystal structure of S-adenosylmethionine decarboxylase (AdoMetDC), and optimize it in Rosetta to obtain the SCAR protein of AdoMetDC;

[0048] 2) Use AutoDockVina to carry out the docking calculation of covalent compounds, and dock the corresponding AdoMetDC covalent inhibitor molecule in the PDB code 3DZ5 into the SCAR protein structure of AdoMetDC, the conformation is as shown in the figure figure 2 As shown, the docked conformation matches well with the crystal structure conformation.

Embodiment 2

[0050] 1) Delete the pyruvyl (Pyr) 68 residue in the crystal structure of S-adenosylmethionine decarboxylase (AdoMetDC), and optimize it in Rosetta to obtain the SCAR protein of AdoMetDC;

[0051] 2) Use AutoDockVina to carry out the docking calculation of covalent compounds, and dock the corresponding AdoMetDC covalent inhibitor molecule in PDB code 1I72 into the SCAR protein structure of AdoMetDC, the conformation is as shown in the figure image 3 As shown, the docked conformation matches well with the crystal structure conformation.

Embodiment 3

[0053] 1) Delete the pyruvyl (Pyr) 68 residue in the crystal structure of S-adenosylmethionine decarboxylase (AdoMetDC), and optimize it in Rosetta to obtain the SCAR protein of AdoMetDC;

[0054] 2) Use AutoDockVina to carry out the docking calculation of covalent compounds, and dock the AdoMetDC covalent inhibitor molecule corresponding to the PDB code 1I79 into the SCAR protein structure of AdoMetDC. The conformation is as shown in the figure Figure 4 As shown, the docked conformation matches well with the crystal structure conformation.

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Abstract

The invention belongs to the field of biomedicine and particularly relates to a computer screening method for small molecular covalent inhibitors and an application of the method to the screening of S-adenosylmethionine decarboxylase covalent inhibitors. According to the method, in computer-aided screening and design processes of covalent inhibitors, steric hindrance of a protein receptor is reduced or eliminated first and then the protein receptor is used for screening, design and modification of the covalent inhibitors or covalent binding molecules. According to the application of the method to the screening of the S-adenosylmethionine decarboxylase covalent inhibitors, pyruvoyl 68 residues in an S-adenosylmethionine decarboxylase crystal structure are removed and optimization is performed in Rosetta software to obtain an optimized protein crystal structure; docking calculation is performed on small molecules to obtain docking calculation results; and the calculation results are screened to obtain the small molecular covalent inhibitors. According to the method and the application thereof, the perfect docking calculation method for numerous non-covalent inhibitors can be widely used, so that the screening, optimization and discovery of the covalent inhibitors can be greatly accelerated.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a computer screening method for small molecule covalent inhibitors and its application in screening covalent inhibitors of S-adenosylmethionine decarboxylase. Background technique [0002] For a long time, in clinical and basic research, small molecular compounds have been widely used as drugs or regulatory molecules to treat diseases or study biological systems. These small molecular compounds can bind to target proteins in a covalent or non-covalent manner. However, covalent compounds were usually avoided in past rational drug screening and design because early researchers worried that covalent compounds would have large "off-target" effects and cause large side effects. Because of this, the past computer-aided screening methods were basically optimized for the docking of non-covalent compounds for screening, design, optimization and evaluation of the binding of non-cova...

Claims

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Application Information

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IPC IPC(8): G06F19/16
CPCG16B15/00
Inventor 刘森
Owner CHINA THREE GORGES UNIV
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