Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego, 30, 16163 Genova, Italy.
J Chem Inf Model. 2014 Feb 24;54(2):362-6. doi: 10.1021/ci4006063. Epub 2014 Jan 30.
Small molecules used in fragment-based drug discovery form multiple, promiscuous binding complexes difficult to capture experimentally. Here, we identify such binding poses and their associated energetics and kinetics using molecular dynamics simulations on AmpC β-lactamase. Only one of the crystallographic binding poses was found to be thermodynamically favorable; however, the ligand shows several binding poses within the pocket. This study demonstrates free-binding molecular simulations in the context of fragment-to-lead development and its potential application in drug design.
在基于片段的药物发现中使用的小分子形成多种、混杂的结合复合物，难以通过实验捕捉。在这里，我们使用 AmpC β-内酰胺酶的分子动力学模拟来识别这些结合构象及其相关的能量学和动力学。只有一个晶体学结合构象被发现是热力学有利的；然而，配体在口袋内显示出几个结合构象。这项研究展示了片段到先导开发背景下的自由结合分子模拟及其在药物设计中的潜在应用。
