Inhibitors of PIM-1 Kinase: A Computational Analysis of the Binding Free Energies of a Range of Imidazo [1,2-b] Pyridazines
Inhibitors of PIM-1 Kinase: A Computational Analysis of the Binding Free Energies of a Range of Imidazo [1,2-b] Pyridazines
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DOI：
10.1021/ci9003514
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发表时间：
2010-03-01
影响因子：
5.6
通讯作者：
Burton, Neil A.
中科院分区：
文献类型：
--
作者：
Doudou, Slimane;Sharma, Raman;Burton, Neil A.
采用计算方法分析了PIM-1激酶竞争性咪唑[1,2-b]吡啶嗪抑制剂与纳米摩尔活性的结合。分子动力学模拟使用伞式采样来确定平均力的势已经被用来准确地预测这些抑制剂的相对自由结合能，从-4.3到-9.5千卡摩尔（-1），与之前的实验分析中观察到的趋势非常一致。抑制剂的相对活性不能由活性位点内的任何单一效应或相互作用来解释，只有在考虑总自由能时才能完全再现，包括铰链区域外的相互作用和在活性位点使用显式溶剂的重要贡献。估计了富甘氨酸磷酸结合环（p环）位移的平均力的潜力，并表明这是这些配体结合的一个重要特征。
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.