效力
化学
酶
立体化学
作用机理
非竞争性抑制
动力学
药物发现
酶动力学
基质(水族馆)
一氧化氮合酶
生物化学
体外
活动站点
生物
物理
量子力学
生态学
作者
Tristan S. Maurer,M A Tabrizi-Fard,H L Fung
标识
DOI:10.1002/1520-6017(200011)89:11<1404::aid-jps4>3.0.co;2-
摘要
Mechanism-based enzyme inactivators (MBEIs) have unique kinetic actions that make predictions of potency, selectivity, and potential for metabolic drug interactions more complex than for competitive antagonists. We have derived a mathematical relationship that links the influence of substrate concentration and binding constant ([S] and K(m), respectively), inhibitor concentration and binding constant ([I] and K(I), respectively), and inactivation rate constant (k(inact)) to enzyme activity (v) and maximal activity (V(max)) at any time (t). The kinetic behavior of this relationship was validated in murine-macrophage cell cultures using MBEIs of nitric oxide synthase (NOS). This initial equation was also used in the derivation of a new relationship that directly links the kinetic parameters of mechanism-based inactivation to inhibitory potency at a particular time (IC((t))(50)). Using this direct relationship, we observed that the predicted rank inhibitory potency of a series of MBEIs was improved over that predicted by the K(I) parameter alone. These relationships offer a fundamental understanding of the kinetics of MBEI action and may be useful in the evaluation of these compounds during the discovery process.
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