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Humanized hexokinase 2 small-molecule inhibitor and application thereof

A technology of glycokinase and medicinal salt, which is applied in the field of biochemical pharmaceuticals, and can solve problems such as adverse reactions, low therapeutic activity, and instability

Inactive Publication Date: 2021-06-04
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are disadvantages such as low therapeutic activity, instability, and obvious adverse reactions (Salani B et al. Sci Rep-UK.2013,3:2070.), and it is still necessary to find improved new HK2 inhibitors

Method used

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  • Humanized hexokinase 2 small-molecule inhibitor and application thereof
  • Humanized hexokinase 2 small-molecule inhibitor and application thereof
  • Humanized hexokinase 2 small-molecule inhibitor and application thereof

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Experimental program
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Effect test

Embodiment 1

[0017] 1. High-throughput virtual screening method for small molecule compound LY2019-001

[0018] (1) Virtual screening based on molecular docking

[0019] Download the crystal structure of hexokinase 2 (PDB code: 5HEX) from the protein structure database PDB, optimize the structure, add charges and hydrogen atoms, select its inhibitor binding pocket, and use the Glide module of Schrödinger software to obtain the crystal structure from both Chemdiv and specs. High-throughput virtual screening based on molecular docking was performed among more than 1.3 million compounds provided by a compound database. Finally, 49 compounds were reserved in the Chemdiv database, and 13 compounds were reserved in the Specs database. A total of 62 compounds (see the following structural formulas) were used for the next enzyme level activity inhibition experiment.

[0020]

[0021]

[0022]

[0023]

[0024] 2. The inhibitory effect of 62 small molecule compounds obtained by virtual...

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Abstract

The invention provides a small-molecule inhibitor taking human hexokinase 2 as a target spot and application of the small-molecule inhibitor, and belongs to the technical field of pharmacy. According to the invention, hexokinase 2 is used as a receptor, an inhibitor binding pocket of hexokinase 2 is selected, molecular docking is carried out by using a Glide program, virtual screening is carried out from more than 1,600,000 compounds to obtain the small-molecule inhibitor LY2019-001 of targeting human hexokinase 2, and enzyme activity inhibition experiments and MTT cell proliferation inhibition experiments are carried out; and the inhibition effect of the compound LY2019-001 on hexokinase 2 and the growth inhibition effect of the compound LY2019-001 on cervical cancer cells HeLa, liver cancer cells HepG2 and lung cancer cells A549 are verified. The found small molecules and pharmaceutical salts thereof can provide a basis for new drug research and development for treating diseases related to hexokinase 2, such as liver cancer, lung cancer, endometrial cancer, breast cancer, ovarian cancer, pancreatic cancer or prostate cancer. The structure of the lead compound can be further optimized, and the lead compound has a relatively good application prospect.

Description

technical field [0001] The invention belongs to the technical field of biochemical pharmacy, and in particular relates to the discovery of a small-molecule inhibitor targeting hexokinase 2 (HK2) that inhibits the activity of human hexokinase 2, and discusses the effect of the discovered small-molecule inhibitor on cervical cancer cells. Growth inhibitory effect of HeLa, liver cancer cells HepG2 and lung cancer cells A549. Background technique [0002] As early as the beginning of the 20th century, Warburg et al. found that unlike most cells, even under the condition of sufficient oxygen supply, tumor cells choose to convert pyruvate directly into lactic acid (ie, the glycolysis pathway) as the main energy production method. Especially in the rapidly growing malignant tumor cells, the ratio of glycolysis is higher. This phenomenon is called "Warburg effect". Hexokinase (Hexokinase, HK) is the rate-limiting enzyme that catalyzes the first step of the glycolysis pathway. It ca...

Claims

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Application Information

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IPC IPC(8): A61K31/404A61P35/00
CPCA61K31/404A61P35/00
Inventor 刘焕香谈硕彦袁苗苗刘瑞娟郭婧筠彭立增姚小军
Owner LANZHOU UNIVERSITY
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