Interpreting steep dose-response curves in early inhibitor discovery
Interpreting steep dose-response curves in early inhibitor discovery
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DOI：
10.1021/jm061103g
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发表时间：
2006-12-14
影响因子：
7.3
通讯作者：
Shoichet, Brian K.
中科院分区：
文献类型：
--
作者：
Shoichet, Brian K.
许多筛选命中抑制酶与陡峭的剂量反应曲线，这被认为是病理性的。三种模型可以解释这些曲线：多位点结合，抑制剂相变，或化学计量抑制所造成的高酶的Kd比。混杂的聚集剂，其中陡峭的曲线是常见的实验表明，这些曲线归因于化学计量的抑制，这预示着IC 50应随酶浓度线性变化。筛选中大多数陡峭的剂量-反应曲线可能是由于这种效应。
Many screening hits inhibit enzymes with steep dose-response curves, which are considered pathological. Three models might explain these curves: multisite binding, an inhibitor phase transition, or stoichiometric inhibition caused by a high enzyme to K-d ratio. Experiments with promiscuous aggregators, for which steep curves are common, suggest that these curves owe to stoichiometric inhibition, which predicts that IC50 should vary linearly with enzyme concentration. Most steep dose-response curves in screening may be due to this effect.