阅读说明：本技术 三七皂苷r1作为几丁质酶抑制剂的新用途 (New use of notoginsenoside R1 as chitinase inhibitor ) 是由 田洋 杨扬 盛军 史崇颖 贺水莲 陶亮 杨茗茸 于 2019-12-26 设计创作，主要内容包括：本发明公开了三七皂苷R1作为几丁质酶抑制剂的新用途,本发明通过基于药效团匹配的反向找靶技术进行三七皂苷R1活性靶点的虚拟筛选,以及计算机模拟分子对接并通过体外几丁质酶活性抑制试验验证发现了三七皂苷R1的一个新作用靶点蛋白几丁质酶,三七皂苷R1对几丁质酶具有较强的抑制作用,可以应用于几丁质酶抑制剂药物的制备并应用于相关疾病的治疗,其能对深入阐明三七皂苷R1的生物活性机制,以及为针对相应靶标所适用的疾病类型精准用药或配合用药奠定必要的研究基础。(The invention discloses a new application of notoginsenoside R1 as a chitinase inhibitor, which is characterized in that pseudo-screening of a notoginsenoside R1 active target is carried out by reverse targeting technology based on pharmacophore matching, computer-simulated molecular docking and in-vitro chitinase activity inhibition tests prove that a new action target protein chitinase of notoginsenoside R1 is found, and the notoginsenoside R1 has stronger inhibition effect on chitinase, can be applied to preparation of chitinase inhibitor medicines and treatment of related diseases, can deeply clarify the biological activity mechanism of the notoginsenoside R1, and lays a necessary research foundation for accurate medicine or matched medicine of disease types applicable to corresponding targets.)

1. The new application of the notoginsenoside R1 is characterized in that the notoginsenoside R1 is used as chitinase inhibitors.

Technical Field

The invention relates to the field of medicines, in particular to a new application of notoginsenoside R1 as a chitinase inhibitor.

Background

Notoginseng radix is plant of Panax of Araliaceae, and has effects of nourishing, strengthening, promoting blood circulation, removing blood stasis, relieving swelling and pain, and stopping bleeding, Notoginseng radix total saponin is main effective component of Notoginseng radix, and ginsenoside Rb1, Rg1 and notoginsenoside R1 are main active monomers of Notoginseng radix saponin. Wherein, the notoginsenoside R1 has good regulating and protecting effects on various systems, organs and tissues, and particularly, the notoginsenoside R1 has obvious activity in reducing blood fat, protecting cardiovascular and cerebrovascular vessels and improving immunity. In recent years, the notoginsenoside R1 which is a specific saponin component of panax notoginseng is often used as an important index in the research and development of some new drugs, but many fields are needed to be further explored aiming at the pharmacological action and mechanism of the monomer R1, so that a new action target of the notoginsenoside R1 is searched, and important reference values are possibly provided for the explanation of the action mechanism of the treatment effect and the drug development.

Reverse targeting is an important method for effectively and conveniently screening novel compound action targets and discovering novel target mechanisms of old drugs in recent development. A series of target fishing methods and databases based on pharmacophore model matching are created. Compared with high-throughput screening of pharmacological experiments, the method has the characteristics of rapidness and economy, and new action targets of a series of compounds are discovered and verified by pharmacological activity. The method for screening the target spots in high flux has higher prediction accuracy of action mechanism through molecular docking verification. The research and development process of new drugs of companies and research institutions is greatly promoted.

The chitinase inhibitor is used as a target point for designing bacteriostatic agents, antifungal agents, insecticides, potential lung immunomodulators and anti-allergic asthma medicaments, and the development of the high-efficiency chitinase inhibitor has very important significance for resisting bacterial fungal infection, preventing and treating agricultural pests and resisting allergic asthma. In the last decade, bacterial, fungal, nematode, insect and human chitinase research has made outstanding progress in the fields of biology and chemical biology. Although the chitinase has no direct medicinal action relation with human diseases, the chitinase is highly expressed in blood of patients infected with chronic inflammation and various degenerative diseases. Whether the inhibition of chitinase is beneficial in the treatment of chronic diseases in humans is a very promising area of research. Recently, the above hypothesis has been strongly demonstrated in studies on the activity of chitinase inhibitors used for pulmonary fibrosis and osteolytic bone disease. Research aiming at osteolytic bone diseases shows that the cell line of a patient with multiple myeloma bone disease has high-level CHIT1 activity, and when bortezomib is used for treating osteolytic bone diseases, the bortezomib inhibits the activities of CHIT1 and TKL40, so that the osteolysis and bone resorption of the cell line of the osteolytic patient are reduced, wherein the activity of CHIT1 is reduced, and the expression level of mRNA of CHIT1 is also reduced. The chitinase can be used as a treatment target of multiple myeloma bone diseases, and the development of a novel chitinase inhibitor has important significance for treating the multiple myeloma bone diseases. At present, the application of the notoginsenoside R1 as a chitinase inhibitor is not reported.

Disclosure of Invention

In view of the above problems, the present invention is directed to: a safe and reliable chitinase inhibitor is searched by a reverse targeting technology, and a new choice is provided for developing new chitinase inhibitor drugs.

The technical characteristics for realizing the invention are as follows:

new use of notoginsenoside R1 as chitinase inhibitor is provided.

The application of the notoginsenoside R1 as chitinase inhibitors comprises notoginsenoside R1 and one or more than two auxiliary materials.

The invention has the beneficial effects that:

the invention discovers a new target of notoginsenoside R1, namely, the notoginsenoside R1 has obvious inhibitory activity on chitinase and is similar to the compound allosamidin (IC) with chitinase inhibitory activity reported at present₅₀＝128μM),acetazolamide(IC₅₀164. mu.M) and 8-chlorothiophylline (IC)₅₀410 mu M), the activity is obviously improved, and the method has stronger development and utilization values.

The notoginsenoside R1 can be used for treating diseases such as multiple myeloma bone disease and the like by inhibiting the activity of chitinase, provides a new choice for developing a new chitinase inhibitor, lays a necessary research foundation for deeply understanding the mechanism of the notoginsenoside R1 for inhibiting the biological activity of the chitinase and accurately or cooperatively using diseases suitable for corresponding targets.

Drawings

FIG. 1 is a molecular characteristic diagram of notoginsenoside R1 and its matching situation with chitinase pharmacophore after pharmmpper pharmacophore matching screening, wherein, (a) is notoginsenoside R1 molecules and molecular characteristics; (b) notoginseng radix saponin R1 and pharmacophore model matching graph;

FIG. 2: (a) the space docking simulation 3D picture of the notoginsenoside R1 and the chitinase is shown, (b) the picture is enlarged, the interaction site can be seen, and (c) the space docking simulation 2D picture of the notoginsenoside R1 and the chitinase is shown;

FIG. 3 shows the inhibition of chitinase by notoginsenoside R1 at different concentrations.

Detailed Description

The present invention will be described in further detail with reference to examples.