School of Chemistry, University of Manchester, Manchester, United Kingdom.
J Chem Inf Model. 2010 Mar 22;50(3):368-79. doi: 10.1021/ci9003514.
The binding of a selection of competitive imidazo [1,2-b] pyridazine inhibitors of PIM-1 kinase with nanomolar activity has been analyzed using computational methods. Molecular dynamics simulations using umbrella sampling to determine a potential of mean force have been used to accurately predict the relative free energies of binding of these inhibitors, from -4.3 to -9.5 kcal mol(-1), in excellent agreement with the trends observed in previous experimental assays. The relative activity of the inhibitors could not be accounted for by any single effect or interaction within the active site and could only be fully reproduced when the overall free energies were considered, including important contributions from interactions outside the hinge region and using explicit solvent in the active site. The potential of mean force for the displacement of the glycine-rich phosphate binding loop (P-loop) has also been estimated and shown to be an important feature in the binding of these ligands.
使用计算方法分析了具有纳摩尔活性的 PIM-1 激酶的一系列竞争性咪唑并[1,2-b]哒嗪抑制剂的结合情况。使用伞状采样确定平均力势能的分子动力学模拟已被用于准确预测这些抑制剂的相对结合自由能，范围为-4.3 至-9.5 kcal mol(-1)，与先前实验测定中观察到的趋势非常吻合。抑制剂的相对活性不能仅用活性位点内的任何单一效应或相互作用来解释，只有当考虑到整体自由能时，包括铰链区域外相互作用的重要贡献以及在活性位点中使用显式溶剂，才能完全再现。还估计了置换富含甘氨酸的磷酸盐结合环（P 环）的平均力势能，并且表明这是这些配体结合的重要特征。
