Application of Free Energy Perturbation (FEP) Methodology for Predicting the Binding Affinity of Macrocyclic JAK2 Inhibitor Analogues of Pacritinib

Pacritinib, an orally bioavailable macrocyclic inhibitor of Janus Kinase 2, has shown efficacy for the treatment of myelofibrosis. Due to the synthetic challenges associated with synthesizing macrocyclic analogues, we applied electrostatic complementarity, 3D-field QSAR, and free energy perturbation methods for the profiling of a set of known ligands with a view to developing a prioritization method for selecting new macrocyclic designs for synthesis. The importance of understanding the 3D conformation and flexibility of a ligand is demonstrated, with these effects having a significant implication on the accuracy of predictions.

帕瑞替尼（Pacritinib）是一种口服生物可利用的贾纳斯激酶2（Janus Kinase 2）大环抑制剂，在骨髓纤维化（myelofibrosis）的治疗中已展现出确切疗效。鉴于大环类似物的合成存在诸多挑战性难题，我们采用静电互补性、三维场定量构效关系（3D-field QSAR）以及自由能微扰（Free Energy Perturbation）方法，对一系列已知配体开展表征分析，以期开发一套优先级筛选方法，用于遴选可用于合成的新型大环分子设计方案。本研究证实了了解配体三维构象与柔性的重要性，此类结构特征对预测结果的准确性具有显著影响。