Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?
Is Ring Breaking Feasible in Relative Binding Free Energy Calculations?
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DOI：
10.1021/acs.jcim.5b00057
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发表时间：
2015-04-01
影响因子：
5.6
通讯作者：
Mobley, David L.
中科院分区：
文献类型：
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作者：
Liu, Shuai;Wang, Lingle;Mobley, David L.
我们的兴趣是基于分子k模拟的相对结合自由能（RBFE）计算。这些都是有前途的工具，在药物发现的铅优化，计算结合自由能的变化，由于修改的铅化合物。然而，在“炼金术”的框架芸香计算，sorbe类型的突变有可能引入错误的计算结合自由能。在这里，我们探讨这种错误在几个不同的模型结合计算的magninide。我们发现，一些计算涉及环断裂有显着的错误，这些错误是特别大的桥环系统。由于误差是配体应变的函数，这是不可预测的提前，我们认为，环断裂应尽可能避免。
Our interest is relative binding free energy (RBFE) Calculations based on molecular k simulations. These are promising tools for lead optimization in drug discovery, computing changes in binding free energy due to modifications of a lead compound. However, in the "alchemical' framework for RUE calculations, sorbe types of mutations have the potential to introduce error into the computed binding free energies. Here we explore the magninide of this error in several different model binding calculations. We find that some of the calculations involving ring breaking have significant errors, and these errors are especially large in bridged ring systems. Since the error is a function of ligand strain, which is impredictablein advance, we believe that ring breaking should be avoided when possible.