Mechanistic basis of enzyme-targeted drugs

被引:187
作者
Robertson, JG [1 ]
机构
[1] Softzymic Inc, Princeton, NJ 08540 USA
关键词
D O I
10.1021/bi050247e
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Enzymes offer unique opportunities for drug design that are not available to cell surface receptors, nuclear hormone receptors, ion channels, transporters, and DNA. Here, we review the variety of inhibition mechanisms for enzyme-targeted drugs, and establish an enzyme target database for drugs currently marketed in the United States. From an analysis of the FDA Orange Book, there are 317 marketed drugs that work by inhibiting an enzyme. These drugs inhibit 71 enzymes, including 48 human, 13 bacterial, five viral, four fungal, and one protozoal enzyme. Among the 317 drugs, 65% either undergo reactive chemistry in the active site of the target enzyme or contain a structural motif related to the substrate. Among the 71 enzyme targets, 25 are irreversibly inhibited by drugs, and 19 of the 25 irreversibly inhibited enzymes are covalently modified by the drug. In two additional cases, the drug forms a covalent complex with the substrate, and in three more cases, the drug traps a covalent enzyme-substrate intermediate. Four of the 71 enzymes are inhibited by transition-state analogues. Moreover, advanced methods for determining transition-state structure now offer the opportunity for direct drug design without resorting to expensive random testing campaigns. A full appreciation of enzyme mechanisms sets enzymes apart as a specialized class of targets for highly directed drug design.
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收藏
页码:5561 / 5571
页数:11
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