Intraligand Hydrophobic Interactions Rationalize Drug Affinities for Peptidyl-Prolyl Cis-Trans Isomerase Protein
Intraligand Hydrophobic Interactions Rationalize Drug Affinities for Peptidyl-Prolyl Cis-Trans Isomerase Protein
复制标题
DOI：
10.1021/jp110585p
复制
发表时间：
2011-05-19
影响因子：
3.3
通讯作者：
Procacci, Piero
中科院分区：
文献类型：
--
作者：
Bizzarri, Marco;Marsili, Simone;Procacci, Piero
使用具有溶质扭转回火的复制交换模拟方法，在本体溶液中测定具有不同抑制常数的三种FK 506相关药物的构象景观。用分子力学方法评价了重要药物构象与FKBP 12蛋白的能量适应性。结果表明，实验亲和力对肽基脯氨酰顺反异构酶蛋白（FKBP 12）的分析配体似乎是正相关的观察到的人口的特定椅子结构的药物哌啶环在本体溶液中。这种观察是合理的基础上，这种结构，稳定的立体特异性分子内疏水相互作用，允许形成一对蛋白质-配体氢键结合。
The conformational landscape of three FK506-related drugs with disparate inhibition constants is determined in bulk solution using a replica exchange simulation method with solute torsional tempering. Energetic fitness of important drug conformations with respect to the FKBP12 protein is evaluated by molecular mechanics. Results show that the experimental affinity toward peptidyl-prolyl cis-trans isomerase protein (FKBP12) of the analyzed ligands appears to be positively correlated to the observed population of specific chair structures of the drug piperidinic ring in bulk solution. This observation is rationalized on the basis that such structures, stabilized by stereospecific intramolecular hydrophobic interactions, allows the formation of a pair of protein-ligand hydrogen bonds upon binding.