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Cathepsin K inhibitor containing naphthoquinone and phenanthrenequinone structures, composition and application thereof

A technology of cathepsin and inhibitors, which is applied in the field of medicine, can solve the problems of tumor cell apoptosis, achieve the effects of increasing bone density, inhibiting the activity of human osteoclasts, and improving bone structure characteristics and physiological state

Pending Publication Date: 2021-02-02
SHANGHAI MUNICIPAL CENT FOR DISEASE CONTROL & PREVENTION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] β-lapachone is a natural naphthoquinone compound that has anti-tumor effects. It induces tumor cell apoptosis by inducing a large amount of ROS in tumor cells. There is no report that it has the effect of inhibiting cathepsin K.

Method used

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  • Cathepsin K inhibitor containing naphthoquinone and phenanthrenequinone structures, composition and application thereof
  • Cathepsin K inhibitor containing naphthoquinone and phenanthrenequinone structures, composition and application thereof
  • Cathepsin K inhibitor containing naphthoquinone and phenanthrenequinone structures, composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preliminary Screening of Cathepsin K Inhibitors

[0034] The identification of cathepsin K inhibitors was carried out by examining the ability of compounds to inhibit the binding of cathepsin K to the fluorescently labeled synthetic substrate Z-FR-MCA.

[0035] 1 Experimental materials

[0036] The monomeric compound β-lapachone was purchased from Merck; menatetrenone and menadione heptaquinone were purchased from Sigma; the substrate Z-FR-MCA was purchased from WAKO, Japan.

[0037] 2 Experimental methods

[0038] The inhibitor was diluted with 100mM sodium acetate buffer (pH5.5, containing 2.5mM DTT and 2.5mM EDTA) to a concentration of 25μM, and added to a 96-well plate with a final reaction volume of 200uL. Add final 100, 75, 25, 15, 5μM) CatK with a final concentration of 5nM and incubate for 5 minutes, then add 5μL substrate 1mM Z-FR-MCA solution to start the reaction, and detect the fluorescence signal (divergent light wavelength 460nm, absorption li...

Embodiment 2

[0043] Example 2: Molecular docking of vitamin K2 and cathepsin K

[0044] Use the libdock molecular docking method in Discovery studio 2016 software to investigate the compound and cathepsin K (1ATK) protein for rigid docking.

[0045] 1 Experimental method:

[0046] The LibDock score is used as the core index to characterize the best binding position of the compound. The higher the LibDock score, the higher the predicted activity of the small molecule binding to the receptor. In addition, the number of hydrogen bonds between the ligand and the receptor was analyzed by DS2016 software, and the amino acid residues that made an important contribution to the ligand binding were found.

[0047] 2 Experimental results

[0048] For libdock molecular docking in Discovery studio 2016 software, vitamin K2 docking scores were 128 for MK4 and 119 for MK7, reflecting a strong docking effect.

[0049] by two-dimensional plane figure 1 It can be seen that there are obvious hydrogen bo...

Embodiment 3

[0051] Example 3: Influence of Inhibitors on the Activity of Cathepsin K

[0052] Cathepsin K inhibitors inhibit cathepsin K activity primarily through its ability to degrade the activity of natural substrates collagen fibers, elastic fibers, and thyroglobulin.

[0053] 1 Experimental materials

[0054] Monomer compound β-lapachone was purchased from merck company; Menadione tetraenyl and menadione heptaquinone were purchased from Sigma company; Chondroitin sulfate A (C4-S), E-64 and pepsin were purchased from Sigma, USA company; type I collagen was purchased from Affymetrix Company of the United States; microporous filter membrane centrifuge tubes were purchased from Amico Millipore Company.

[0055] 2 Experimental methods

[0056] 2.1 Collagen fiber degradation activity

[0057] Using gel electrophoresis (SDS-PAGE), soluble type I collagen was dissolved in 100mM sodium acetate buffer (pH 5.5, containing 2.5mM DTT and 2.5mM EDTA) to a final concentration of 0.6mg / ml, follo...

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Abstract

The invention provides a cathepsin K inhibitor containing naphthoquinone and phenanthrenequinone structures, a composition and application thereof. The inhibitor is used for preparing a medicine for treating diseases with cathepsin K as a target; a compound acts on an active site of the cathepsin K, has remarkable activity of inhibiting enzyme substrate collagen degradation or elastic fibrin degradation or thyroglobulin degradation, and can be used for preparing drugs for treating diseases characterized by abnormal expression or activation of the cathepsin K, including thyroid diseases, cardiovascular diseases and bone diseases, specifically hyperthyroidism, osteoporosis, gum diseases (gingivitis and periodontitis), rheumatoid arthritis and the like; researches prove that beta-lapachone significantly inhibits the degradation of cathepsin K substrate collagen, elastic fibers and thyroglobulin; and menatetrenone and heptaene menadione have strong molecular action with the cathepsin K, sothat the combination of the cathepsin K and substrate collagen fibers can be remarkably inhibited, and the collagen degradation is inhibited.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a cathepsin K inhibitor containing naphthoquinone and phenanthrenequinone structures, its composition and application. Background technique [0002] Cathepsin K belongs to the cysteine ​​protease family and is closely related to many major diseases such as osteoporosis, arthritis, and thyroid abnormalities. It is a target protease that has attracted much attention in recent years. Cathepsin K is not only characteristically present in osteoclasts, but also in skin, heart, skeletal muscle, lung, thyroid and other tissues, and mainly plays a role in degrading collagen, elastin and thyroglobulin in the body. Cathepsin K knockout mice, in addition to significantly increased bone density, also showed symptoms such as lung airway damage, lung or skin fibrosis, and thyroglobulin (Tg) release of thyroxine dysfunction. [0003] β-lapachone is a natural naphthoquinone compound...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61K31/352A61K31/122A61K45/06A61P5/16A61P19/10A61P1/02A61P19/02A61P29/00
CPCA61K45/00A61K31/352A61K31/122A61K45/06A61P5/16A61P19/10A61P1/02A61P19/02A61P29/00A61K2300/00
Inventor 薛黎明蒋益萍卢大胜汪国权金玉娥冯超徐佳乐
Owner SHANGHAI MUNICIPAL CENT FOR DISEASE CONTROL & PREVENTION
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