Department of Bioengineering, Stanford University, Stanford, CA, USA.
J R Soc Interface. 2012 Jul 7;9(72):1409-37. doi: 10.1098/rsif.2011.0843. Epub 2012 May 2.
Marketed drugs frequently perform worse in clinical practice than in the clinical trials on which their approval is based. Many therapeutic compounds are ineffective for a large subpopulation of patients to whom they are prescribed; worse, a significant fraction of patients experience adverse effects more severe than anticipated. The unacceptable risk-benefit profile for many drugs mandates a paradigm shift towards personalized medicine. However, prior to adoption of patient-specific approaches, it is useful to understand the molecular details underlying variable drug response among diverse patient populations. Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms correlated with differential therapeutic outcomes. Together these advances provide the opportunity to examine how altered protein structures arising from genetic differences affect protein-drug interactions and, ultimately, drug response. In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions. Next, we describe the impact of coding mutations on protein structures and drug response. Finally, we highlight tools for analysing protein structures and protein-drug interactions and discuss their application for understanding altered drug responses associated with protein structural variants.
市售药物在临床实践中的表现常常不如其获批所依据的临床试验。许多治疗性化合物对大量被处方的患者群体无效；更糟糕的是，相当一部分患者出现了比预期更严重的不良反应。许多药物不可接受的风险效益比要求向个体化医学范式转变。然而，在采用个体化方法之前，了解不同患者群体中药物反应差异的分子细节是很有用的。在过去的十年中，结构基因组学的进展导致了可用的药物靶蛋白三维结构的爆炸式增长，而药物遗传学的努力则提供了与不同治疗结果相关的多态性的见解。这些进展共同提供了机会来研究由于遗传差异而产生的改变的蛋白质结构如何影响蛋白质-药物相互作用，并最终影响药物反应。在这篇综述中，我们首先总结了蛋白质靶标的结构特征和药物相互作用的常见机制。接下来，我们描述了编码突变对蛋白质结构和药物反应的影响。最后，我们强调了分析蛋白质结构和蛋白质-药物相互作用的工具，并讨论了它们在理解与蛋白质结构变体相关的改变的药物反应方面的应用。
