Tokarski J S, Hopfinger A J
Laboratory of Molecular Modeling and Design (M/C-781), University of Illinois at Chicago, College of Pharmacy 60612-7231, USA.
J Chem Inf Comput Sci. 1997 Jul-Aug;37(4):792-811. doi: 10.1021/ci970006g.
A methodology is presented and applied in which the accurate estimation of ligand-receptor binding thermodynamics is achieved by formulating the calculation as a QSAR problem. When the receptor geometry is known, the free energy force field (FEFF) ligand-receptor binding energy terms can be calculated and used as independent variables in constructing FEFF 3D-QSARs. The FEFF 3D-QSAR analysis of a series of transition state inhibitors of renin was carried out. From a statistical analysis of the free energy contributions to the binding process, FEFF 3D-QSARs were constructed that reveal the change in solvation free energy upon binding and the intramolecular vacuum internal energy of the ligand in the unbound state are the most significant FEFF terms in determining the binding free energy, delta G. Other terms, such as ligand stretching, bending, and torsion energy changes, the intermolecular van der Waals interaction energy, and change in ligand conformational entropy upon binding, are also found to make significant contributions in some FEFF 3D-QSAR delta G models and in delta H and delta S binding models. Overall, a relatively small number of the thermodynamic contributions to the ligand-receptor binding process dominates the thermodynamics of binding in a given model.
本文提出并应用了一种方法，该方法通过将计算表述为一个定量构效关系（QSAR）问题来实现对配体-受体结合热力学的准确估计。当受体几何结构已知时，可以计算自由能力场（FEFF）配体-受体结合能项，并将其用作构建FEFF 3D-QSARs中的自变量。对一系列肾素过渡态抑制剂进行了FEFF 3D-QSAR分析。通过对结合过程中自由能贡献的统计分析，构建了FEFF 3D-QSARs，结果表明，结合时溶剂化自由能的变化以及未结合状态下配体的分子内真空内能是决定结合自由能ΔG的最重要的FEFF项。还发现其他项，如配体的伸缩、弯曲和扭转能量变化、分子间范德华相互作用能以及结合时配体构象熵的变化，在一些FEFF 3D-QSAR ΔG模型以及ΔH和ΔS结合模型中也有显著贡献。总体而言，在给定模型中，对配体-受体结合过程的热力学贡献中相对较少的一部分主导了结合的热力学。
