An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge,RSC Medicinal Chemistry

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An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-04-19 00:00:00 , DOI: 10.1039/c8md00166a
Ugo Perricone ₁ , Maria Rita Gulotta _{1,

2} , Jessica Lombino _{1,

2} , Barbara Parrino ₂ , Stella Cascioferro ₂ , Patrizia Diana ₂ , Girolamo Cirrincione ₂ , Alessandro Padova ₁

Affiliation

Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein–ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host–guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein–protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognised as vital to the discovery of selective protein–protein interaction modulators. The use of a dynamic overview on how the host–guest recognition occurs and of the relative conformational modifications induced allows researchers to optimise small molecules and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein–protein interactions.

中文翻译：

近期分子动力学应用作为药物化学工具应对不可成药位点挑战的概述

由于硬件和软件解决方案的发展以及算法的改进，分子动力学（MD）变得越来越流行，这使得研究人员能够扩大计算规模以加快计算速度。 MD 模拟通常用于通过随时间的能量分布分析来解决蛋白质折叠问题或蛋白质-配体复合物的稳定性。近年来，能够深入探索势能表面（PES）的新工具的开发使研究人员能够专注于结合识别过程的动态性质和结合诱导的蛋白质构象变化。此外，现代方法已被证明在计算主客体识别过程背后的一些动力学和热力学参数方面是有效和可靠的。从所有这些考虑出发，为了将MD整合到药物发现的虚拟筛选过程中，已经做出了一些努力。事实上，从 MD 中检索到的知识可以用作筛选活动早期阶段构建药效基团或对接约束以及定义关键特征的起点，以揭示隐藏的结合模式并帮助优化先导化合物的分子结构。基于这些结果，研究人员现在使用MD作为一种宝贵的工具来发现和靶向以前被认为不可成药的结合位点，包括蛋白质-蛋白质相互作用和蛋白质表面上的变构位点。事实上，MD 的使用已被认为对于发现选择性蛋白质-蛋白质相互作用调节剂至关重要。通过动态概述主客体识别如何发生以及诱导的相对构象修饰，研究人员可以优化能够在两种蛋白质之间的裂缝内紧密相互作用的小分子和小肽。在这篇综述中，我们的目标是介绍 MD 作为一种集成工具的最新应用，用于合理设计能够调节不可成药靶点的小分子或小肽，例如变构位点和蛋白质-蛋白质相互作用。

更新日期：2018-04-19

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