Zhang Xiaohua, Perez-Sanchez Horacio, Lightstone Felice C
Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory (LLNL), Livermore, CA, United States.
Bioinformatics and High Performance Computing Research Group, Department of Computer Science, Universidad Católica San Antonio de Murcia (UCAM), Spain.
Curr Top Med Chem. 2017;17(14):1631-1639. doi: 10.2174/1568026616666161117112604.
A high-throughput virtual screening pipeline has been extended from single energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring to ensemble-average MM/GBSA rescoring. The correlation coefficient (R2) of calculated and experimental binding free energies for a series of antithrombin ligands has been improved from 0.36 to 0.69 when switching from the single-structure MM/GBSA rescoring to ensemble-average one. The electrostatic interactions in both solute and solvent are identified to play an important role in determining the binding free energy after the decomposition of the calculated binding free energy. The increasing negative charge of the compounds provides a more favorable electrostatic energy change but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic energy change, which results in a better binding affinity. A highly hydrophobic ligand is determined by the docking program to be a non-specific binder.
Our results have demonstrated that it is very important to keep a few top poses for rescoring, if the binding is non-specific or the binding mode is not well determined by the docking calculation.
高通量虚拟筛选流程已从单一能量最小化结构的分子力学/广义玻恩表面积（MM/GBSA）重新打分扩展到系综平均MM/GBSA重新打分。当从单结构MM/GBSA重新打分切换到系综平均重新打分时，一系列抗凝血酶配体的计算结合自由能与实验结合自由能的相关系数（R2）从0.36提高到了0.69。在对计算出的结合自由能进行分解后，发现溶质和溶剂中的静电相互作用在决定结合自由能方面起着重要作用。化合物负电荷的增加提供了更有利的静电能变化，但对溶剂化自由能产生了更高的惩罚。这种惩罚由静电能变化补偿，从而导致更好的结合亲和力。对接程序确定一种高度疏水的配体为非特异性结合剂。
我们的结果表明，如果结合是非特异性的或对接计算不能很好地确定结合模式，保留几个最佳构象进行重新打分非常重要。
