Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs
Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs
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DOI：
10.1007/978-1-4939-7465-8_13
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Matosiuk, Dariusz
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文献类型：
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作者：
Bartuzi, Damian;Kaczor, Agnieszka A.;Matosiuk, Dariusz
从药理学的角度来看，变构调节剂可以呈现出优于正构配体的许多优点。越来越多的新工具和实验数据的可用性提供了一个诱人的机会，应用计算方法来改善已知的调制器和设计新颖的。然而，最近在理解变构的复杂性方面的进展增加了对具有所需性质的调制器的设计中所涉及的问题的认识。更深入地了解现象，如探针依赖性，改变信号偏差与配体结构的微小变化，以及微妙的内源性变构因子的影响原来是根本的。这些效应使得具有精确药理学结果的调节剂的设计成为一项非常具有挑战性的任务，并且需要在整个设计过程中加以考虑。在本章中，我们专注于计算药物设计工作中靶向GPCR变构位点的细微差别，特别是对接，虚拟筛选和分子动力学的应用。
From the pharmacological point of view, allosteric modulators may present numerous advantages over orthosteric ligands. Growing availability of novel tools and experimental data provides a tempting opportunity to apply computational methods to improve known modulators and design novel ones. However, recent progress in understanding of complexity of allostery increases awareness of problems involved in design of modulators with desired properties. Deeper insight into phenomena such as probe dependence, altering signaling bias with minor changes in ligand structure, as well as influence of subtle endogenous allosteric factors turns out to be fundamental. These effects make the design of a modulator with precise pharmacological outcome a very challenging task, and need to be taken into consideration throughout the design process. In this chapter, we focus on nuances of targeting GPCR allosteric sites in computational drug design efforts, in particular with application of docking, virtual screening, and molecular dynamics.