Groebe Duncan R
Abbott Laboratories, R4PN/J35, 200 Abbott Park Road, Abbott Park, IL 60064, USA.
Drug Discov Today. 2006 Jul;11(13-14):632-9. doi: 10.1016/j.drudis.2006.05.010.
The benefit of using positive allosteric modulators of protein function in the therapy of human diseases is becoming more apparent. The advantage of positive allosteric modulators is that they can possess specificity and selectivity profiles as well as concentration-independent limits on activity that can significantly reduce off-target effects in vivo. However, many current screening paradigms are not designed to discover positive allosteric modulators, and modulators that are discovered serendipitously can be overlooked during the hit-picking process. The conditions needed to discover positive allosteric modulators in a HTS are reasonable and simple to implement, generally requiring consideration of the ligand concentration in a screen. Other considerations in the screening for positive allosteric modulators can be derived from the analysis of simple kinetic schemes that describe the interactions of ligands and modulators with different protein targets.
在人类疾病治疗中使用蛋白质功能的正变构调节剂的益处正变得愈发明显。正变构调节剂的优势在于它们能够具有特异性和选择性特征，以及对活性的浓度非依赖性限制，这可显著降低体内的脱靶效应。然而，许多当前的筛选模式并非设计用于发现正变构调节剂，并且在命中选择过程中，偶然发现的调节剂可能会被忽视。在高通量筛选中发现正变构调节剂所需的条件合理且易于实施，通常需要考虑筛选中的配体浓度。筛选正变构调节剂的其他考虑因素可源自对描述配体和调节剂与不同蛋白质靶点相互作用的简单动力学方案的分析。
