Institute of Theoretical and Computational Chemistry, Key Laboratory of Mesoscopic Chemistry of MOE, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
J Chem Inf Model. 2010 Jan;50(1):136-45. doi: 10.1021/ci900175n.
The combination of docking and molecular dynamics simulation is used to explain the isoform-specific selectivity between PI3Kalpha and PI3Kgamma, which are two lipid kinases in the class I PI3Ks. The protein flexibility is incorporated in docking the ligands to the ensemble of representative structures extracted from a clustering analysis of the molecular dynamics simulation in explicit aqueous solution. The reported most potent PI3Kalpha inhibitor PIK-75 was studied, and we predicted three possible PIK-75-bound conformations for PI3Kalpha and two for PI3Kgamma. Comparative analysis between the PI3Kalpha and PI3Kgamma docking experiments indicates that the residue Trp780 and Asn782 in PI3Kalpha and the corresponding residues Trp812 and Glu814 in PI3Kgamma in the solvent-accessible region can confer the PI3Kalpha and PI3Kgamma isoform specificity. The predicted bound conformations are further studied in aqueous solution by molecular dynamics simulation. The work provides a possible effective pharmacophore model for PI3Kalpha inhibitor. The dynamic behaviors of the LY294002-bound PI3Ks are studied too.
docking 和分子动力学模拟的结合用于解释 PI3Kalpha 和 PI3Kgamma 之间的同工型特异性选择性，PI3Kalpha 和 PI3Kgamma 是 I 类 PI3Ks 中的两种脂质激酶。将配体对接至从分子动力学模拟的明确水溶液中的聚类分析中提取的代表性结构的集合中时，会合并蛋白质柔性。研究了报道的最有效的 PI3Kalpha 抑制剂 PIK-75，并预测了 PI3Kalpha 的三种可能的 PIK-75 结合构象和 PI3Kgamma 的两种。PI3Kalpha 和 PI3Kgamma 对接实验之间的比较分析表明，PI3Kalpha 溶剂可及区域中的残基 Trp780 和 Asn782 以及 PI3Kgamma 中的相应残基 Trp812 和 Glu814 可以赋予 PI3Kalpha 和 PI3Kgamma 同工型特异性。通过分子动力学模拟进一步研究了预测的结合构象。该工作为 PI3Kalpha 抑制剂提供了一种可能的有效药效团模型。还研究了 LY294002 结合的 PI3Ks 的动态行为。
