Structure-based ligand design to overcome CYP inhibition in drug discovery projects

被引：68

作者：

Branden, Gisela ^{[1
]}

Sjogren, Tove ^{[2
]}

Schnecke, Volker ^{[3
]}

Xue, Yafeng ^{[2
]}

机构：

[1] Univ Gothenburg, Dept Chem & Mol Biol, S-40530 Gothenburg, Sweden

[2] AstraZeneca R&D, Discovery Sci, S-43183 Molndal, Sweden

[3] AstraZeneca R&D, CVMD iMed, S-43183 Molndal, Sweden

来源：

DRUG DISCOVERY TODAY | 2014年 / 19卷 / 07期

关键词：

HUMAN CYTOCHROME P4502C9; METABOLISM PREDICTIONS; FUNCTIONAL RELEVANCE; RITONAVIR ANALOGS; 3A4; BINDING; INSIGHTS; DOCKING; 2D6; P4503A4;

D O I：

10.1016/j.drudis.2014.03.012

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Cytochrome P450 (CYP) enzymes are key players in xenobiotic metabolism, and inhibition of CYPs can therefore result in unwanted drug-drug interactions. Within drug discovery, CYP inhibition can cause delays in the progression of candidate drugs, or even premature closure of projects. During the past decade, a massive effort in the pharmaceutical industry and academic research has produced a wealth of structural information in the CYP field. In this short review, we will describe how structure-based approaches can be used in the pharmaceutical industry to work away from CYP inhibition, with a focus on the opportunities and challenges. We will show two examples from our own work where structural information on CYP2C9 and CYP3A4 inhibitor complexes have been successfully exploited in ongoing drug discovery projects.

引用

页码：905 / 911

页数：7

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