Kuntz I D, Chen K, Sharp K A, Kollman P A
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-0446, USA.
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):9997-10002. doi: 10.1073/pnas.96.18.9997.
We explore the question of what are the best ligands for macromolecular targets. A survey of experimental data on a large number of the strongest-binding ligands indicates that the free energy of binding increases with the number of nonhydrogen atoms with an initial slope of approximately -1.5 kcal/mol (1 cal = 4.18 J) per atom. For ligands that contain more than 15 nonhydrogen atoms, the free energy of binding increases very little with relative molecular mass. This nonlinearity is largely ascribed to nonthermodynamic factors. An analysis of the dominant interactions suggests that van der Waals interactions and hydrophobic effects provide a reasonable basis for understanding binding affinities across the entire set of ligands. Interesting outliers that bind unusually strongly on a per atom basis include metal ions, covalently attached ligands, and a few well known complexes such as biotin-avidin.
我们探讨了对于大分子靶点而言，最佳配体是什么这一问题。对大量最强结合配体的实验数据进行的一项调查表明，结合自由能随着非氢原子数量的增加而增加，初始斜率约为每原子-1.5千卡/摩尔（1卡 = 4.18焦耳）。对于含有超过15个非氢原子的配体，结合自由能随相对分子质量的增加而增加得很少。这种非线性在很大程度上归因于非热力学因素。对主要相互作用的分析表明，范德华相互作用和疏水效应为理解整个配体集合的结合亲和力提供了合理的基础。按每个原子计算结合异常强烈的有趣异常值包括金属离子、共价连接的配体以及一些知名的复合物，如生物素-抗生物素蛋白。
