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[结核分枝杆菌细胞色素P450作为潜在药物靶点的研究进展]

[Research progresses of Mycobacterium tuberculosis cytochrome P450s as a potential drug target].

作者信息

Lu Yun, Qiao Feng, You Xue-Fu, Yang Xin-Yi

出版信息

Yao Xue Xue Bao. 2014 Apr;49(4):427-34.

Abstract

Identification and validation of a new target is one of the most important steps for new antituberculosis (TB) drug discovery. Researches have shown that Mycobacterium tuberculosis (Mtb) encodes 20 CYP450 enzymes which play important roles in the synthesis and metabolism of lipid, cholesterol utilization, and the electron transport of respiratory chain in Mtb. With the critical roles within the organism as well as the protein structures of six Mtb CYP450 enzymes being clarified, some of them have been highlighted as potential anti-tuberculosis targets. In this paper, the phylogenetic analysis, the structural features, and the enzymatic functions of Mtb CYPs, as well as the mechanism of interactions with selective inhibitors such as azole antifungal agents for the CYPs have been reviewed and summarized. The druggability of the CYPs has also been analyzed for their further utility as targets in high throughput screening and rational design of more selective inhibitors.

摘要

鉴定和验证新靶点是新型抗结核药物研发的重要步骤之一。研究表明,结核分枝杆菌(Mtb)编码20种细胞色素P450(CYP450)酶,这些酶在Mtb的脂质合成与代谢、胆固醇利用以及呼吸链电子传递中发挥重要作用。随着其中六种Mtb CYP450酶在生物体中的关键作用以及蛋白质结构得以阐明,它们中的一些已被视为潜在的抗结核靶点。本文对Mtb CYP450酶的系统发育分析、结构特征、酶功能,以及它们与唑类抗真菌剂等选择性抑制剂的相互作用机制进行了综述和总结。还分析了CYP450酶作为靶点在高通量筛选以及更具选择性抑制剂的合理设计中的可药用性,以便进一步加以利用。

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