Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics
Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics
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DOI：
10.1021/acs.jmedchem.6b00399
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发表时间：
2016-12-08
影响因子：
7.3
通讯作者：
Carlson, Heather A.
中科院分区：
文献类型：
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作者：
Ghanakota, Phani;Carlson, Heather A.
识别蛋白质表面上的结合热点是基于结构的药物发现的主要兴趣，以评估追求蛋白质靶点的易处理性或驱动先导化合物的改进效力。检测这些区域的计算方法传统上依赖于在没有天然水性环境的情况下将探针分子能量最小化到静态蛋白质构象上。高性能计算的进步现在允许我们使用分子动力学（MD）模拟来评估热点。MD模拟整合了蛋白质的灵活性和水的复杂作用，从而提供了一个更现实的评估复杂的动力学和热力学在发挥作用。在这篇综述中，我们描述了各种共溶剂为基础的MD技术的发展，并强调了无数的潜在应用，这些技术在计算药物开发。
Identifying binding hotspots on protein surfaces is of prime interest in structure-based drug discovery, either to assess the tractability of pursuing a protein target or to drive improved potency of lead compounds. Computational approaches to detect such regions have traditionally relied on energy minimization of probe molecules onto static protein conformations in the absence of the natural aqueous environment. Advances in high performance computing now allow us to assess hotspots using molecular dynamics (MD) simulations. MD simulations integrate protein flexibility and the complicated role of water, thereby providing a more realistic assessment of the complex kinetics and thermodynamics at play. In this review, we describe the evolution of various cosolvent-based MD techniques and highlight a myriad of potential applications for such technologies in computational drug development.