Institute for Computational Sciences and Technology , SBI Building, Quang Trung Software City , Tan Chanh Hiep Ward, District 12, Ho Chi Minh City , Vietnam.
Department of Theoretical Physics, Faculty of Physics and Engineering Physics , Ho Chi Minh University of Science, Vietnam National University , 227 Nguyen Van Cu, Dist. 5 , Ho Chi Minh City , Vietnam.
J Phys Chem B. 2018 May 3;122(17):4693-4699. doi: 10.1021/acs.jpcb.8b02137. Epub 2018 Apr 20.
Binding affinity of a small ligand to a receptor is the important quantity in drug design, and it might be characterized by different quantities. The most popular one is the binding free energy, which can be estimated by several methods in conventional molecular dynamics simulation. So far in steered molecular dynamics (SMD), one can use either the rupture force or nonequilibrium pulling work as a measure for binding affinity. In this paper, we have shown that the nonequilibrium binding free energy Δ G, obtained by Jarzynski's equality at a finite pulling speed, has good correlation with experimental data on inhibition constants, implying that this quantity can be used as a good scoring function for binding affinity. A similar correlation has also been disclosed for binding and unbinding free energy barriers. Applying the SMD method to unbinding of 23 small compounds from the binding site of β-lactamase protein, a bacteria-produced enzyme, we have demonstrated that the rupture or unbinding time strongly correlates with experimental data with correlation level R ≈ 0.84. As follows from the Jarzynski's equality, the rupture time depends on the unbinding barrier exponentially. We show that Δ G, the rupture time, and binding and unbinding free energy barriers are good descriptors for binding affinity. Our observation may be useful for fast screening of potential leads as the SMD simulation is not time-consuming. On the basis of nonequilibrium simulation, we disclosed that, in agreement with the experiment, the binding time is much longer than the unbinding one.
小分子配体与受体的结合亲和力是药物设计中的重要参数，它可以用不同的参数来描述。最常用的参数是结合自由能，它可以通过传统分子动力学模拟中的几种方法来估算。到目前为止，在牵引分子动力学（SMD）中，可以使用断裂力或非平衡牵引功作为结合亲和力的度量。在本文中，我们表明，在有限的牵引速度下通过雅可比等式获得的非平衡结合自由能 ΔG 与抑制常数的实验数据具有很好的相关性，这意味着该参数可作为结合亲和力的良好评分函数。结合和离解自由能势垒也存在类似的相关性。将 SMD 方法应用于从β-内酰胺酶蛋白结合位点释放的 23 种小分子化合物，我们证明了断裂或离解时间与实验数据具有很强的相关性，相关系数 R≈0.84。根据雅可比等式，断裂时间与离解势垒呈指数关系。我们表明，ΔG、断裂时间和结合及离解自由能势垒是结合亲和力的良好描述符。我们的观察结果可能有助于快速筛选潜在的先导化合物，因为 SMD 模拟并不耗时。基于非平衡模拟，我们揭示了与实验结果一致的情况，即结合时间远长于离解时间。
