Bartuzi Damian, Kaczor Agnieszka A, Matosiuk Dariusz
Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling Lab, Medical University of Lublin, 4A Chodźki Str., PL20093, Lublin, Poland.
Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modelling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki Str., PL20093, Lublin, Poland.
Methods Mol Biol. 2018;1705:297-319. doi: 10.1007/978-1-4939-7465-8_13.
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.
从药理学角度来看，变构调节剂可能比正构配体具有诸多优势。新型工具和实验数据的日益丰富为应用计算方法改进已知调节剂并设计新型调节剂提供了诱人的机会。然而，近期在变构复杂性理解方面的进展提高了对设计具有所需特性的调节剂所涉及问题的认识。深入了解诸如探针依赖性、配体结构微小变化导致信号偏向改变以及内源性变构微妙因素的影响等现象至关重要。这些效应使得设计具有精确药理学结果的调节剂成为一项极具挑战性的任务，并且在整个设计过程中都需要加以考虑。在本章中，我们将重点关注在计算药物设计中靶向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。
