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首页> 外文期刊>Journal of Computer-Aided Molecular Design >Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure
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Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure

机译：使用自动 RE-EDS 采样程序计算支架跳跃型变换的相对自由能

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The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free-energy difference between pairs of ligands. Thus, the comparison of multiple ligands requires the construction of a "state graph", in which the compounds are connected by alchemical transformations. The computational cost can be optimized by reducing the state graph to a minimal set of transformations. However, this may require individual adaptation of the sampling strategy if a transformation process does not converge in a given simulation time. In contrast, path-free methods like replica-exchange enveloping distribution sampling (RE-EDS) allow the sampling of multiple states within a single simulation without the pre-definition of alchemical transition paths. To optimize sampling and convergence, a set of RE-EDS parameters needs to be estimated in a pre-processing step. Here, we present an automated procedure for this step that determines all required parameters, improving the robustness and ease of use of the methodology. To illustrate the performance, the relative binding free energies are calculated for a series of checkpoint kinase 1 inhibitors containing challenging transformations in ring size, opening/closing, and extension, which reflect changes observed in scaffold hopping. The simulation of such transformations with RE-EDS can be conducted with conventional force fields and, in particular, without soft bond-stretching terms.
机译：计算不同化合物之间的相对自由能差异在药物设计中起着重要作用，以确定给定蛋白质靶标的有效结合剂。基于分子动力学模拟的最严格的方法估计配体对之间的自由能差异。因此，多个配体的比较需要构建一个“状态图”，其中化合物通过炼金术转化连接。通过将状态图减少到一组最小的转换，可以优化计算成本。但是，如果转换过程在给定的仿真时间内没有收敛，则可能需要对采样策略进行单独调整。相比之下，副本交换包络分布采样 （RE-EDS） 等无路径方法允许在单个模拟中对多个状态进行采样，而无需预先定义炼金术过渡路径。为了优化采样和收敛，需要在预处理步骤中估计一组RE-EDS参数。在这里，我们提出了此步骤的自动化程序，该程序可确定所有必需的参数，从而提高方法的稳健性和易用性。为了说明性能，计算了一系列检查点激酶 1 抑制剂的相对结合自由能，这些抑制剂包含环大小、打开/关闭和延伸的挑战性转变，这反映了在支架跳跃中观察到的变化。使用RE-EDS模拟这种转变可以在常规力场下进行，特别是在没有软键拉伸项的情况下进行。

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