Lamb M L, Jorgensen W L
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, USA.
J Med Chem. 1998 Oct 8;41(21):3928-39. doi: 10.1021/jm980062o.
The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 as well as for their potential as building blocks for chemical inducers of protein dimerization. Relative binding affinities were computed and analyzed for ligands differing by a phenyl ring, an external phenyl or pyridyl substituent, and a pipecolyl or prolyl ring. Such results are, in general, valuable for inhibitor optimization and, in the present case, bring into question some of the previously reported binding data.
利用蒙特卡罗统计力学模拟中的自由能微扰技术，研究了六种FK506结合蛋白（FKBP12）抑制剂的结合特性和溶液相性质。这些非免疫抑制性分子因其与FKBP12结合时的神经营养活性以及作为蛋白质二聚化化学诱导剂的潜在构建模块而受到关注。计算并分析了具有苯环、外部苯基或吡啶基取代基以及哌啶基或脯氨酰环差异的配体的相对结合亲和力。总体而言，这些结果对于抑制剂优化具有重要价值，在当前情况下，对一些先前报道的结合数据提出了质疑。
