Accurate calculation of the absolute free energy of binding for drug molecules.
Accurate calculation of the absolute free energy of binding for drug molecules.
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DOI：
10.1039/c5sc02678d
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发表时间：
2016-01-14
期刊：
影响因子：
8.4
通讯作者：
Biggin PC
中科院分区：
文献类型：
--
作者：
Aldeghi M;Heifetz A;Bodkin MJ;Knapp S;Biggin PC
基于分子动力学和热力学循环的自由能计算准确地再现了不同溴结构域抑制剂的实验亲和力。几十年来，结合亲和力的准确预测一直是计算化学的中心目标，但仍然难以捉摸。尽管取得了很好的进展，但在药物发现背景下使用所需的准确性并没有始终如一地实现药物样分子。在这里，我们进行绝对自由能计算的基础上的一组不同的抑制剂结合到含溴结构域蛋白4（BRD 4）的热力学循环，并证明可以实现的平均绝对误差为0.6千卡mol-1。我们还显示了类似的精度水平（1.0千卡摩尔-1），可以实现在伪前瞻性的方法。溴结构域是识别乙酰化基序并调节基因转录的表观遗传标记阅读器，并且目前正在研究作为癌症和炎症的治疗靶标。这种前所未有的精确度为预测类药物化合物与靶点的结合自由能提供了令人兴奋的前景。
Free energy calculations based on molecular dynamics and thermodynamic cycles accurately reproduce experimental affinities of diverse bromodomain inhibitors. Accurate prediction of binding affinities has been a central goal of computational chemistry for decades, yet remains elusive. Despite good progress, the required accuracy for use in a drug-discovery context has not been consistently achieved for drug-like molecules. Here, we perform absolute free energy calculations based on a thermodynamic cycle for a set of diverse inhibitors binding to bromodomain-containing protein 4 (BRD4) and demonstrate that a mean absolute error of 0.6 kcal mol–1 can be achieved. We also show a similar level of accuracy (1.0 kcal mol–1) can be achieved in pseudo prospective approach. Bromodomains are epigenetic mark readers that recognize acetylation motifs and regulate gene transcription, and are currently being investigated as therapeutic targets for cancer and inflammation. The unprecedented accuracy offers the exciting prospect that the binding free energy of drug-like compounds can be predicted for pharmacologically relevant targets.