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Application of virtual screening compound as integrin protein alpha v beta 3 antagonist and application of virtual screening compound in preparation of antitumor medicines

An anti-tumor drug, virtual screening technology, applied in the field of anti-tumor drugs

Active Publication Date: 2021-09-17
PEKING UNIV FIRST HOSPITAL
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Problems solved by technology

However, recent advances in other novel peptide sequence peptidomimetics and small molecules have shown that RGD-based targeted therapy is not the end point of research

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  • Application of virtual screening compound as integrin protein alpha v beta 3 antagonist and application of virtual screening compound in preparation of antitumor medicines
  • Application of virtual screening compound as integrin protein alpha v beta 3 antagonist and application of virtual screening compound in preparation of antitumor medicines
  • Application of virtual screening compound as integrin protein alpha v beta 3 antagonist and application of virtual screening compound in preparation of antitumor medicines

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Embodiment Construction

[0028] virtual screening

[0029] The present invention discovers small molecule inhibitors of αvβ3 receptors based on machine learning and molecular docking methods. The αvβ3 integrin inhibitors (1337 molecules) were first downloaded from the pubchem database, and the Decoy dataset was generated at the same time. Split into training set (962 molecules), test set (241 molecules), validation set (134 molecules) and external test set (182 molecules) downloaded from chembl. Molecular fingerprint descriptors were generated by Morgan2. Then use the machine learning model RF and SVM algorithm to establish a screening model.

[0030] The screening model was used to conduct a preliminary screening of 350,000 small molecules in the SPECS database, and then use the αvβ3 crystal structure (1L5G and 6MK0) downloaded from the PDB to perform FRED molecular docking and Libdock molecular docking from Discovery Studio. The invention uses the active pocket defined by the original ligand in t...

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Abstract

The invention provides application of a virtual screening compound as an integrin protein alpha v beta 3 antagonist and application of the virtual screening compound in preparation of antitumor medicines. The virtual screening compound has a structure as shown in a formula I, a formula II or a formula III. According to the application, surface plasma resonance detection is carried out on three small molecule compounds which are obtained by screening and are shown in formulas I to III to test the binding activity thereof, and the result shows that KD values of interaction between the compounds shown in the formula I, the formula II and the formula III and integrin protein alpha v beta 3 are 1.58*10M<-7>, 2.72*10M<-7> and 9.64*10M <-7> respectively, which indicates that the compounds have extremely high binding activity with the protein alpha v beta 3. An anti-tumor active cell evaluation test shows that the three compounds obtained through virtual screening have obvious anti-tumor activity on various tumor cells.

Description

technical field [0001] The invention belongs to the technical field of antitumor drugs, and in particular relates to the application of a virtual screening compound as an antagonist of integrin protein αvβ3 and its application in the preparation of antitumor drugs. Background technique [0002] Integrin proteins are the major mediators of cell adhesion on the cell surface. In particular, integrin αvβ3 has been widely concerned and deeply studied as a target for cancer therapy. Because it mediates a variety of angiogenic processes during tumor development. The peptide sequence Arg-Gly-Asp (RGD) exists in many endogenous integrin ligands, such as fibronectin, vitronectin, and related proteins such as extracellular matrix (ECM), and has also been widely used in the field of tumor diagnosis for therapeutic Drugs such as the cyclic RGD peptide cilengitide have entered clinical trials for the treatment of various cancers, but unfortunately the current RGD-based drugs have failed...

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Application Information

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IPC IPC(8): A61K31/416A61K31/165A61K31/403A61P35/00
CPCA61K31/416A61K31/165A61K31/403A61P35/00
Inventor 崔一民庞晓丛张智夏杰何旭谷延伦刘振明张峻岭解染
Owner PEKING UNIV FIRST HOSPITAL