分子动力学
药物发现
结合亲和力
亲缘关系
FKBP公司
结合位点
片段(逻辑)
血浆蛋白结合
化学
结合能
计算生物学
计算机科学
计算化学
立体化学
物理
生物
算法
生物化学
受体
核物理学
作者
Albert C. Pan,Huafeng Xu,Timothy Palpant,David E. Shaw
标识
DOI:10.1021/acs.jctc.7b00172
摘要
A quantitative characterization of the binding properties of drug fragments to a target protein is an important component of a fragment-based drug discovery program. Fragments typically have a weak binding affinity, however, making it challenging to experimentally characterize key binding properties, including binding sites, poses, and affinities. Direct simulation of the binding equilibrium by molecular dynamics (MD) simulations can provide a computational route to characterize fragment binding, but this approach is so computationally intensive that it has thus far remained relatively unexplored. Here, we perform MD simulations of sufficient length to observe several different fragments spontaneously and repeatedly bind to and unbind from the protein FKBP, allowing the binding affinities, on- and off-rates, and relative occupancies of alternative binding sites and alternative poses within each binding site to be estimated, thereby illustrating the potential of long time scale MD as a quantitative tool for fragment-based drug discovery. The data from the long time scale fragment binding simulations reported here also provide a useful benchmark for testing alternative computational methods aimed at characterizing fragment binding properties. As an example, we calculated binding affinities for the same fragments using a standard free energy perturbation approach and found that the values agreed with those obtained from the fragment binding simulations within statistical error.
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