Divergent Modes of Enzyme Inhibition in a Homologous Structure-Activity Series
Divergent Modes of Enzyme Inhibition in a Homologous Structure-Activity Series
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DOI：
10.1021/jm9009229
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发表时间：
2009-08-27
影响因子：
7.3
通讯作者：
Renslo, Adam R.
中科院分区：
文献类型：
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作者：
Ferreira, Rafaela S.;Bryant, Clifford;Renslo, Adam R.
A（锁定屏幕识别出可逆的非共价抑制剂（例如，I）的寄生虫半胱氨酸蛋白酶cruzain。化学优化的I导致了一系列的恶二唑具有可解释的SAR和效力高达500倍大于1。随后对SAR系列的详细研究表明，恶二唑类的许多成员（令人惊讶的是，还有1）通过不同的抑制模式（竞争性或通过胶体聚集）起作用，这取决于所采用的测定条件。
A (locking screen identified reversible, noncovalent inhibitors (e.g., I) of the parasite cysteine protease cruzain. Chemical optimization of I led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending oil the assay conditions employed.