Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
Int J Mol Sci. 2019 Oct 30;20(21):5410. doi: 10.3390/ijms20215410.
Based on the up-regulation of the proviral integration site of the Moloney murine leukemia virus (Pim) kinase family (Pim1, 2, and 3) observed in several types of leukemias and lymphomas, the development of pan-Pim inhibitors is an attractive therapeutic strategy. While only PIM447 and AZD1208 have entered the clinical stages. To elucidate the interaction mechanisms of three Pim kinases with PIM447 and AZD1208, six Pim/ligand systems were studied by homology modeling, molecular docking, molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy calculation. The residues of the top group (Leu44, Val52, Ala65, Lys67, and Leu120 in Pim1) dominated the pan-Pim inhibitors binding to Pim kinases. The residues of the bottom group (Gln127, Asp128, and Leu174 in Pim1) were crucial for Pims/PIM447 systems, while the contributions of these residues were decreased sharply for Pims/AZD1208 systems. It is likely that the more potent pan-Pim inhibitors should be bound strongly to the top and bottom groups. The residues of the left, right and loop groups were located in the loop regions of the binding pocket, however, the flexibility of these regions triggered the protein interacting with diverse pan-Pim inhibitors efficiently. We hope this work can provide valuable information for the design of novel pan-Pim inhibitors in the future.
基于 Moloney 鼠白血病病毒（Pim）激酶家族（Pim1、2 和 3）原病毒整合位点在几种类型的白血病和淋巴瘤中上调的观察结果，开发泛 Pim 抑制剂是一种有吸引力的治疗策略。虽然只有 PIM447 和 AZD1208 进入了临床阶段。为了阐明三种 Pim 激酶与 PIM447 和 AZD1208 的相互作用机制，通过同源建模、分子对接、分子动力学（MD）模拟和分子力学/广义 Born 表面积（MM/GBSA）结合自由能计算研究了六个 Pim/配体系统。通过同源建模、分子对接、分子动力学（MD）模拟和分子力学/广义 Born 表面积（MM/GBSA）结合自由能计算研究了六个 Pim/配体系统。通过同源建模、分子对接、分子动力学（MD）模拟和分子力学/广义 Born 表面积（MM/GBSA）结合自由能计算研究了六个 Pim/配体系统。处于顶部组（Pim1 中的 Leu44、Val52、Ala65、Lys67 和 Leu120）的残基主导着泛 Pim 抑制剂与 Pim 激酶的结合。底部组（Pim1 中的 Gln127、Asp128 和 Leu174）的残基对于 Pims/PIM447 系统至关重要，而对于 Pims/AZD1208 系统，这些残基的贡献急剧下降。很可能更有效的泛 Pim 抑制剂应该与顶部和底部基团紧密结合。左侧、右侧和环组的残基位于结合口袋的环区域，然而，这些区域的灵活性触发了蛋白质与不同的泛 Pim 抑制剂有效相互作用。我们希望这项工作能为未来设计新型泛 Pim 抑制剂提供有价值的信息。
