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Drug screening method based on structural fragment, tetracyclic diterpenoid compound and application

A technology of structural fragments and screening methods, applied in the field of biomedicine, can solve problems such as high cost, high cost, and low efficiency, and achieve the effects of improving rationality, increasing success rate, and reducing costs

Pending Publication Date: 2022-04-29
HUAZHONG AGRI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the above deficiencies or improvement needs of the prior art, the present invention provides a drug screening method based on structural fragments, tetracyclic diterpenoids and applications, the purpose of which is to select and determine natural product molecular biology by observing structural fragments. The core structure and polycyclic structure closely related to the activity are used as landmark structural fragments, and it is not necessary to confirm the crystal structure of the receptor protein for compound structure screening, thereby solving the problem that the existing drug discovery methods based on structural fragments require the identification of receptor proteins. Crystal structure diagrams to determine iconic structural fragments, a technical problem with high cost, high cost and low efficiency

Method used

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  • Drug screening method based on structural fragment, tetracyclic diterpenoid compound and application
  • Drug screening method based on structural fragment, tetracyclic diterpenoid compound and application
  • Drug screening method based on structural fragment, tetracyclic diterpenoid compound and application

Examples

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Effect test

Embodiment 1

[0079] Example 1 Using the drug screening method based on structural fragments provided by the present invention, the lead molecule Ori is improved to screen anti-inflammatory active molecules, such as figure 1 shown, including the following steps:

[0080] (1) Use the molecule to be improved with specific biological activity as the lead molecule, fragment its molecular structure into structural fragments, screen out the mother nucleus structure as the mother nucleus screening marker structure fragment, and screen out the polycyclic structure as the binding screening marker Structural fragments; specifically:

[0081] Select Ori as the natural product molecule to be improved, that is, the lead molecule;

[0082] Ori is an active diterpene natural product extracted from the Lamiaceae Camellia genus Orion, with a structure such as figure 2 shown. Although Ori has good anti-inflammatory and anti-tumor activities, the low biological content and complex chemical synthesis pathw...

Embodiment 2

[0096] Example 2 The effect of the tetracyclic diterpene compound ST-4 and its precursor candidate small molecule provided by the present invention on the viability of tumor cells and macrophages includes the following steps:

[0097] S1. Cell recovery and culture: raise the temperature of the water bath to 37°C in advance, and then take the frozen cells (A549, HepG2 and MCF-7; iBMDMs and THP-1) out of the liquid nitrogen tank and place them in a 37°C water bath until it melts. After the cells are thawed, transfer them to a 50ml centrifuge tube, then add 10ml of normal complete medium (90% DMEM+10FBS+1% double antibody) for A549, HepG2, MCF-7 and iBMDMs, and add its proprietary complete medium for THP-1 cells The medium (90% RPMI-1640+10% FBS+1% double antibody+0.05mM / L β-mercaptoethanol) was gently mixed and centrifuged at 1000rpm for 5min. Discard the supernatant, add 10ml of fresh normal medium to resuspend the cells, then transfer to an appropriate culture volume, and pla...

Embodiment 3

[0102] Example 3 In vitro anti-inflammatory activity evaluation of the tetracyclic diterpene compound ST-4 provided by the present invention:

[0103] 1) Isolation and cultivation of mouse bone marrow-derived macrophages (BMDMs): In the animal room, 6-week-old mice were taken, and the mice were killed by cervical dislocation, and the two hind legs of the mice were taken out with sterile scissors. Next, except for the muscles and leg bones, the mouse corpses and other garbage were placed in the mouse mortuary. Take the mouse leg bone to the ultra-clean bench between the cells, soak the scissors and tweezers in 75% alcohol, prepare the medium, PBS, 20ml syringe and 0.65mm medical needle. Wash the mouse leg bone three times with PBS, fill the 20mL syringe with DMEM medium, and replace it with a 0.65mm medical needle, grab the bone with tweezers, cut it from both ends with scissors, and blow the bone marrow to the 50ml centrifuge tube, repeated several times, until the bone marro...

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Abstract

The invention discloses a drug screening method based on structural fragments, tetracyclic diterpenoid compounds and application. The method comprises the following steps: (1) fragmenting and decomposing a leading molecular structure into structural fragments, and screening out a parent nucleus structure and a polycyclic structure; (2) searching a set of compounds as an alternative raw material molecule set by taking a parent nucleus and a polycyclic structure fragment as screening conditions; and (3) selecting one or more raw material molecules, comparing the selected raw material molecules with the lead molecules, and performing functional group modification on the raw material molecules to obtain design molecules, so that the structural similarity of the design molecules and the lead molecules is higher than that of the raw material molecules and the lead molecules. According to the drug screening method based on the structural fragment, a receptor protein crystal diagram is not needed, the efficiency of drug molecule development can be improved, and the cost of drug molecule screening can be reduced. According to the present invention, oridonin (Ori) is adopted as the lead molecule, and the designed drug molecule has significant anti-inflammatory and anti-metabolic syndrome activity;

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically relates to a drug screening method based on structural fragments, tetracyclic diterpenoids and applications. Background technique [0002] The field of drug research and development has always been a key area based on the major cause of human health. Since the rise of combinatorial chemistry in the 1990s, drug researchers in various countries have devoted a lot of manpower and material resources to drug research and development based on combinatorial chemistry. However, in recent years, The output was not as high as expected. Natural products and their derivatives have always been the focus of attention of workers in the field of drug research and development. Through the data analysis of new drugs approved by the FDA in the past 35 years from 1981 to 2014, it can be found that nearly 63% of new drugs are derived from natural products or based on natural products. This data direc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G16B15/30G16C20/50C07H15/256C07D311/00C07C62/32C07C49/743A61P29/00A61P3/00A61P3/10A61P19/02A61P19/06
CPCG16B15/30G16C20/50C07H15/256C07D311/00C07C62/32C07C49/743A61P29/00A61P3/00A61P3/10A61P19/02A61P19/06
Inventor 胡学博陈强周波
Owner HUAZHONG AGRI UNIV
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