Screening method and application of farnesyl pyrophosphate synthase FPPS inhibitor

A technology of farnesyl pyrophosphate and screening method, applied in the field of medicine, can solve the problems of high cost, low non-bone tissue targeting, low efficiency, etc., and achieve the advantages of enhancing curative effect, improving drug polarity, and increasing blood drug concentration. Effect

Active Publication Date: 2019-09-27
JIANGSU INST OF NUCLEAR MEDICINE
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Problems solved by technology

[0005] Therefore, the technical problem to be solved in the present invention is to overcome the high polarity and bone affinity of existing bisphosphonic acid FPPS inhibitors, low non-bone tissue targeting, and the inefficiency and low efficiency of

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  • Screening method and application of farnesyl pyrophosphate synthase FPPS inhibitor
  • Screening method and application of farnesyl pyrophosphate synthase FPPS inhibitor
  • Screening method and application of farnesyl pyrophosphate synthase FPPS inhibitor

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Embodiment 1

[0061] This embodiment provides a screening method for farnesyl pyrophosphate synthase FPPS inhibitors, and the screening process is as follows: figure 1 shown, including the following steps:

[0062] 1) FPPS template construction: Obtain the FPPS complex crystal 4QPF from the PDB database (http: / / www.rcsb.org / ), and its crystal resolution is Use the PrepareProtein module in the Discovery studio 3.0 software package to perform dehydration, hydrogenation, de-repeating conformation, and structural processing of missing residues on 4QPF, and compare and confirm it with the complete 1YQ7 crystal structure of the amino acid sequence, such as figure 2 shown. Define the ligand molecule in the FPPS complex crystal 4QPF as the active center, and select the radius of the active center sphere The amino acid residues within the range are the active sites.

[0063] 2) Data set preparation: known active FPPS inhibitors were extracted from the crystal structure of the FPPS complex, the...

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Abstract

The invention provides a screening method of a farnesyl pyrophosphate synthase (FPPS) inhibitor. The screening method comprises the following steps: (1) constructing an FPPS template; (2) preparing a data set; 3) performing virtual screening based on molecular docking; 4) performing virtual screening based on the pharmacophore model; 5) calculating binding energy; 6) integrating the docking scores in the steps 3), 4) and 5), the pharmacophore model FitValue value and the binding energy to obtain the FPPS inhibitor; and 7) carrying out FPPS enzyme activity inhibition experiment on the FPPS inhibitor obtained by virtual screening, and determining the FPPS inhibitor with the structure shown in the formula I. The method gives full play to the advantages of theoretical screening, reduces the blindness of drug synthesis, effectively improves the hit rate of positive drugs, saves manpower, material resources and financial resources, and realizes the new use value of old drugs. The invention further provides application of the FPPS inhibitor obtained through screening in preparation of drugs for treating colon cancer.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a virtual screening method targeting farnesyl pyrophosphate synthase FPPS, the FPPS inhibitor obtained by the method and its application as a medicine for treating colon cancer. Background technique [0002] The mevalonate pathway is a biochemical pathway necessary for a variety of basic products in organisms, mainly including cholesterol, isoprenoids, dolichols and ubiquinones. It has recently been demonstrated that multiple oncogenic pathways ultimately attribute to the mevalonate pathway to maintain cancer cell survival within deregulated metabolic domains. Oncogenic and tumor suppressive pathways are linked to the mevalonate pathway, especially in cancer cells with metabolic abnormalities that upregulate this pathway to maintain cell proliferation. The mevalonate pathway is a highly regulated pathway in non-transformed cells, and any change in the regulatory mechanism will ...

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Application Information

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IPC IPC(8): G16C20/30G16C20/50G16C20/64
CPCG16C20/30G16C20/50G16C20/64
Inventor 刘清竹邱玲林建国吕高超彭莹李珂
Owner JIANGSU INST OF NUCLEAR MEDICINE
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