Pepstatin-derived inhibitors of aspartic proteinases. A close look at an apparent transition-state analogue inhibitor.
Pepstatin-derived inhibitors of aspartic proteinases. A close look at an apparent transition-state analogue inhibitor.
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DOI：
10.1021/jm00381a001
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发表时间：
1985-03
影响因子：
7.3
通讯作者：
D. Rich
中科院分区：
文献类型：
--
作者：
D. Rich
酶抑制剂复合物的物理研究为酶结合的因素和机制提供了越来越精确的图景。酶催化的新概念已经产生，并且治疗重要酶的抑制剂的设计，如降压药卡托普利和依那普利，已经刺激了。这些研究受到过渡态类似物抑制剂假说的显著影响，其中一个方面指出，类似于酶反应过渡态的稳定结构将比酶催化反应的底物结合得更紧密。当x射线晶体数据用于揭示酶的催化机制时，由于其低解离常数，通常认为其他紧密结合抑制剂类似于反应途径中间体，例如过渡态。如果不仔细检查，这些交织在一起的假设可能成为循环论点，导致对酶催化机制的误解和新酶抑制剂的错误设计，其中许多为未来的药物发现提供了相当大的潜力。一种方法是(1)使用的缩写遵循IUPAC-IUB生化命名委员会的建议。其他缩写如下：Sta， 3-羟基-4-氨基-6-甲基庚酸；AHPPA， 3-羟基-4-氨基-5-苯戊酸；Stap, phosphastatine（文献21）；AHPBA， 2-羟基-3-氨基-4-苯基丁酸；DAHOA,(3S, 4S)- 4,8 -二氨基-3-羟基辛酸；Me3Sta， 3-羟基-4-氨基- 3,6 -二甲基庚酸；国标,3-oxo-4-amino-6 -
Physical studies of enzyme-inhibitor complexeshave provided an increasingly precise picture of factors con-tributing to enzyme binding and mechanism. New con-cepts for enzyme catalysis have resulted, and the design of inhibitors of therapeutically important enzymes, such as the antihypertensive drugs captopril1 2 and enalapril, 3 456has been stimulated. These studies have been significantly influenced by the transition-state analogue inhibitor hy-pothesis, 4, 6 one aspect of which states that stable structures resembling the transition state for an enzyme reaction will be bound more tightly than the substrate for the en-zyme-catalyzed reaction. Other tight-binding inhibitors are often assumed, because of their low dissociation con-stants, to resemble a reaction pathway intermediate, such as the transition state, when X-ray crystal data are used to unravel enzyme catalytic mechanisms. If not examined carefully, these intertwined assumptions can become circular arguments, leading to misconceptions about enzyme catalytic mechanisms and to faulty design of inhibitors of new enzymes, many of which offer considerable potential for future drug discovery. 7 One way to approach this (1) Abbreviations used follow the IUPAC-IUB commission on Biochemical Nomenclature recommendation. Additional ab-breviations are as follows: Sta, 3-hydroxy-4-amino-6-methylheptanoic acid; AHPPA, 3-hydroxy-4-amino-5-phenylpentanoic acid; Stap, phosphastatine (ref 21); AHPBA, 2-hydroxy-3-amino-4-phenylbutanoic acid; DAHOA,(3S, 4S)-4, 8-diamino-3-hydroxyoctanoic acid; Me3Sta, 3-hydroxy-4-amino-3, 6-dimethylheptanoic acid; Sto, 3-oxo-4-amino-6-