Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics,The Journal of Physical Chemistry Letters

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Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics
The Journal of Physical Chemistry Letters ( IF 4.8 ) Pub Date : 2018-05-30 00:00:00 , DOI: 10.1021/acs.jpclett.8b01284
Jonah Z. Vilseck ₁ , Kira A. Armacost ₁ , Ryan L. Hayes ₁ , Garrett B. Goh ₁ , Charles L. Brooks _{1,

2}

Affiliation

In this study, we demonstrate the extensive scalability of the biasing potential replica exchange multisite λ dynamics (BP-REX MSλD) free energy method by calculating binding affinities for 512 inhibitors to HIV Reverse Transcriptase (HIV-RT). This is the largest exploration of chemical space using free energy methods known to date, requires only a few simulations, and identifies 55 new inhibitor designs against HIV-RT predicted to be at least as potent as a tight binding reference compound (i.e., as potent as 56 nM). We highlight that BP-REX MSλD requires an order of magnitude less computational resources than conventional free energy methods while maintaining a similar level of precision, overcomes the inherent poor scalability of conventional free energy methods, and enables the exploration of combinatorially large chemical spaces in the context of in silico drug discovery.

中文翻译：

使用多位点λ动力学预测大型组合化学空间中的结合自由能

在这项研究中，我们通过计算512种抑制剂对HIV逆转录酶（HIV-RT）的结合亲和力，证明了偏向性潜在的复制品交换多站点λ动力学（BP-REXMSλD）自由能方法的广泛可扩展性。这是迄今为止使用自由能方法对化学空间进行的最大探索，仅需进行少量模拟即可确定55种针对HIV-RT的新抑制剂设计，预计其效价至少与紧密结合的参考化合物相同（即为56 nM）。我们着重指出，BP-REXMSλD与传统的自由能源方法相比，所需的计算资源要少一个数量级，同时保持相似的精度水平，克服了传统自由能源方法固有的可扩展性差，

更新日期：2018-05-30

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