Screening method and application of farnesyl pyrophosphate synthase FPPS inhibitor

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 ...

AI Technical Summary

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 FPPS-related lead discovery. High cost and other issues, thus providing a virtual screening method for non-bisphosphonate FPPS inhibitors with novel structure, good pharmacokinetic properties, and target specificity and its application in antitumor

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