Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.
J Chem Inf Model. 2023 Apr 24;63(8):2469-2482. doi: 10.1021/acs.jcim.2c01589. Epub 2023 Apr 6.
Janus kinases (JAK), a group of proteins in the nonreceptor tyrosine kinase (NRTKs) family, play a crucial role in growth, survival, and angiogenesis. They are activated by cytokines through the Janus kinase-signal transducer and activator of a transcription (JAK-STAT) signaling pathway. JAK-STAT signaling pathways have significant roles in the regulation of cell division, apoptosis, and immunity. Identification of the V617F mutation in the Janus homology 2 (JH2) domain of JAK2 leading to myeloproliferative disorders has stimulated great interest in the drug discovery community to develop JAK2-specific inhibitors. However, such inhibitors should be selective toward JAK2 over other JAKs and display an extended residence time. Recently, novel JAK2/STAT5 axis inhibitors (N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives) have displayed extended residence times (hours or longer) on target and adequate selectivity excluding JAK3. To facilitate a deeper understanding of the kinase-inhibitor interactions and advance the development of such inhibitors, we utilize a multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach within the Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) program to rank order these inhibitors based on their kinetic properties and further explain the selectivity of JAK2 inhibitors over JAK3. Our approach investigates the kinetic and thermodynamic properties of JAK-inhibitor complexes in a user-friendly, fast, efficient, and accurate manner compared to other brute force and hybrid-enhanced sampling approaches.
Janus 激酶（JAK）是非受体酪氨酸激酶（NRTKs）家族中的一组蛋白，在生长、存活和血管生成中发挥着关键作用。它们通过 Janus 激酶信号转导和转录激活因子（JAK-STAT）信号通路被细胞因子激活。JAK-STAT 信号通路在细胞分裂、细胞凋亡和免疫的调节中起着重要作用。Janus 同源性 2（JH2）结构域中的 V617F 突变导致骨髓增殖性疾病的鉴定，激发了药物发现社区开发 JAK2 特异性抑制剂的极大兴趣。然而，此类抑制剂应针对 JAK2 具有选择性，且对其他 JAK 具有延长的停留时间。最近，新型 JAK2/STAT5 轴抑制剂（N-(1H-吡唑-3-基)嘧啶-2-氨基衍生物）在靶标上表现出延长的停留时间（数小时或更长时间）和足够的选择性，排除了 JAK3。为了更深入地了解激酶-抑制剂相互作用并推进此类抑制剂的开发，我们利用 Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) 程序中的多尺度 Markov 里程碑与 Voronoi 细分 (MMVT) 方法，根据动力学特性对这些抑制剂进行排序，并进一步解释 JAK2 抑制剂对 JAK3 的选择性。与其他暴力和混合增强采样方法相比，我们的方法以用户友好、快速、高效和准确的方式研究了 JAK-抑制剂复合物的动力学和热力学性质。
