Department of Engineering Mechanics, State Key Laboratory of Structural Analysis for Industrial Equipment, and Faculty of Chemical, Environmental, and Biological Science and Technology, Dalian University of Technology, Dalian 116023, China.
Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4273-8. doi: 10.1073/pnas.1301814110. Epub 2013 Feb 25.
Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (ΔG(off)≠). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development.
药物-靶标停留时间（t = 1/k（off），其中 k（off）是离解速率常数）已成为发现更好或最佳类药物的重要指标。然而，很少有人致力于开发能够准确预测该动力学参数或相关参数 k（off）和离解自由能（ΔG（off）≠）的计算方法。在本文中，我们扩展了用于理解蛋白质折叠和功能的能量景观理论，以开发一种普遍适用的计算框架，该框架能够构建完整的配体-靶标结合自由能景观。这使得结合亲和力和结合动力学都能够被准确地估计。我们将该方法应用于模拟抗阿尔茨海默病药物（-）-石杉碱 A 与其靶标乙酰胆碱酯酶（AChE）的结合事件。计算结果与我们同时进行的实验测量非常吻合。所有预测的结合自由能和结合与离解的自由能都与实验数据的偏差小于 1 kcal/mol。该方法还为（-）-石杉碱 A 的结合途径提供了原子分辨率的信息，这可能有助于设计更有效的 AChE 抑制剂。我们希望这种方法能够广泛应用于药物发现和开发。
