College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
J Chem Inf Model. 2010 Oct 25;50(10):1887-98. doi: 10.1021/ci1002679.
Phosphatidylinositol 3-kinase α (PI3Kα) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3Kα kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3Kα, the H1047R mutant of PI3Kα and the γ isoform of PI3K (PI3Kγ). We also investigated the effect of protein flexibility on ligand binding by docking the same set of ligands to conformations of the wt and mutant PI3Kα generated by molecular dynamics simulations. Our data suggests that conformational differences in Gln859, Ser854, Tyr836, and Ser774 between the PI3Kα wt and H1047R mutant may be used to design ligands that are active against both the wt and H1047R mutant isoforms. Gln859, Ser854 and Ser774 may play critical roles in ligand binding to the α isoform H1047R mutant while formation of H-bonds with Ser806 of PI3Kγ may enhance γ-isoform-specific inhibition. In addition to H-bond interactions, structural and size differences in the activation and hydrophobic domains of PI3Kα, PI3Kγ, and the PI3Kα H1047R mutant could be exploited to direct the design of isoform- and/or mutant-specific PI3K inhibitors. Our data provide a reasonable explanation for the activity and selectivity of small molecular PI3K inhibitors and are in good agreement with available experimental and computational data.
磷脂酰肌醇 3-激酶α（PI3Kα）是一种很有前途的抗癌药物设计靶点。在许多肿瘤中观察到催化结构域中的致癌突变 H1047R，它可能通过影响环构象以及膜结合来增强 PI3Kα 激酶活性。我们应用对接方法对 33 种 PI3K 抑制剂进行了研究，这些抑制剂针对野生型（wt）PI3Kα、PI3Kα 的 H1047R 突变体和 PI3K 的 γ 同工型（PI3Kγ）。我们还通过对接分子动力学模拟生成的 wt 和突变 PI3Kα 构象中的同一组配体，研究了蛋白质柔性对配体结合的影响。我们的数据表明，wt 和 H1047R 突变体 PI3Kα 之间 Gln859、Ser854、Tyr836 和 Ser774 的构象差异可用于设计对 wt 和 H1047R 突变体同工型均具有活性的配体。Gln859、Ser854 和 Ser774 可能在配体与α同工型 H1047R 突变体的结合中发挥关键作用，而与 PI3Kγ 的 Ser806 形成氢键可能增强γ同工型特异性抑制。除了氢键相互作用外，PI3Kα、PI3Kγ 和 PI3Kα H1047R 突变体的激活和疏水区的结构和大小差异可用于指导同工型和/或突变体特异性 PI3K 抑制剂的设计。我们的数据为小分子 PI3K 抑制剂的活性和选择性提供了合理的解释，与现有实验和计算数据吻合良好。
