Virtual screening method of targeted IKK beta drug

A virtual screening and drug technology, applied in bioinformatics, instruments, and used to analyze two-dimensional or three-dimensional molecular structures, etc. The effect of application value and prospect

Pending Publication Date: 2020-06-09
SUZHOU UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ursolic acid has problems such as poor solubility and difficulty in being absorbed by the body, which limits its clinical application.

Method used

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  • Virtual screening method of targeted IKK beta drug
  • Virtual screening method of targeted IKK beta drug
  • Virtual screening method of targeted IKK beta drug

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0035] Analysis of the binding effect of ursolic acid and IKKβ by iGEMDOCK molecular docking software

[0036] IKKβ is a receptor, and its three-dimensional crystal structure is derived from the PDB protein database (ID: 4KIK); ursolic acid is a ligand. The iGEMDOCK molecular docking software directly imports receptors and ligands, docking parameter settings: Population Size is set to 200, Generations is set to 70, Number of solutions is set to 2 (below same). The binding energy between ursolic acid and IKKβ was found to be -98.9kcaj / mol, indicating that ursolic acid and IKKβ have a certain binding ability.

[0037] image 3 It is a schematic diagram of molecular docking analysis between ursolic acid and IKKβ. The binding sites between ursolic acid and IKKβ are Leu21, Thr23, Glu97, and Cys99, which are located in the active pocket of IKKβ. , Cys99 site produces hydrogen bonding, and the carboxyl group on the C28 position of ursolic acid produces hydrogen bonding with the Le...

Embodiment 2

[0039] The iGEMDOCK molecular docking software analyzes the binding effect of different side chain groups on the C3 position of ursolic acid and IKKβ

[0040] According to the results of Example 1, the hydroxyl group on the C3 position of ursolic acid is modified with a side chain group, and the selected side chain group R1~11 is shown in Figure 4 (The hydrogen in the side chain group has been omitted, the same below). The iGEMDOCK molecular docking software was used to analyze the binding effect of the modified ursolic acid and IKKβ respectively.

[0041] Taking the side chain groups R2, R6, R9 as an example, Figure 5-7 Schematic diagrams of molecular docking analysis of modified ursolic acid and IKKβ, respectively. It can be seen from the figure that R2, R6, and R9 can all form hydrogen bonds with Glu97 and Cys99. Among them, the amino hydrogen atom of R2 penetrates into the ATP binding region and forms a hydrogen bond with Glu97 and Cys99; the carboxyl hydrogen atom of R...

Embodiment 3

[0047] The iGEMDOCK molecular docking software analyzes the binding effect of different side chain groups on the C28 position of ursolic acid and IKKβ

[0048] According to the result of embodiment 1, the carboxyl group on the C28 position of ursolic acid is carried out side chain group transformation, the side chain group R1 '-14' of selection sees Figure 8 , using iGEMDOCK molecular docking software to analyze the binding effect of the modified ursolic acid and IKKβ respectively.

[0049] Take the side chain group R1', R2', R14' as an example, Figures 9 to 11 Schematic diagrams of molecular docking analysis of modified ursolic acid and IKKβ, respectively. It can be seen from the figure that both the ether group oxygen of R1' and the ester group oxygen of R2' form hydrogen bonds with Thr23, indicating that the side chain group at the C28 position can go deep into the Gly ring and does not interact with the ATP binding region. The carbonyl oxygen atom and amino hydrogen atom...

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Abstract

The embodiment of the invention discloses a virtual screening method of a targeted IKK beta drug, and belongs to the technical field of medicinal chemistry. The method comprises the following steps: by taking ursolic acid as a ligand and IKKbeta (PDB ID: 4KIK) as receptor protein, analyzing a binding site and binding energy of ursolic acid and IKK beta and a binding side chain group of ursolic acid by adopting molecular docking software; analyzing a binding site and binding energy of the modified ursolic acid and IKK beta by adopting molecular docking software; preliminarily screening out a side chain group with a relatively good binding effect; and carrying out molecular modification on ursolic acid to obtain an ursolic acid derivative, and adopting molecular docking software to preliminarily determine a targeted IKKbeta drug. Based on the principle and method of molecular docking, ursolic acid is subjected to side chain group modification, the ursolic acid derivative with good docking capacity is screened out, and the ursolic acid derivative has good application value and prospect in the field of development of antitumor drugs with ursolic acid as a primer.

Description

technical field [0001] The embodiment of the present invention relates to the technical field of medicinal chemistry, in particular to a virtual screening method for drugs targeting IKKβ. Background technique [0002] IKKβ is one of the main members of the IKK family. IKK (IκB kinase, inhibitor kappa B kinase) is a key regulator of the IKK / NF-κB pathway and consists of three subunits: IKKα, IKKβ, and IKKγ. IKKα and IKKβ have kinase domain, which can function as phosphorylation, and IKKγ is the regulatory subunit. Among them, IKKβ phosphorylates Ser32 and Ser36 in the IκBα (inhibitor of NF-κB) molecule and induces its degradation, so that NF-κB dissociates from the complex and then transports to the nucleus to start the transcription of downstream genes. Therefore, IKKβ activates NF-κB Key subunit of the κB classical pathway. While IKKβ activity is regulated by upstream kinases, it also participates in the regulation of target genes related to various diseases, especially i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G16B15/30G16B20/00G16C20/50
CPCG16B15/30G16B20/00G16C20/50
Inventor 郭伟强孙敏轩马志俊
Owner SUZHOU UNIV OF SCI & TECH
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