Braz Natércia F, Slater Martin J, Lang Stuart
New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire SG8 0SS, U.K.
ACS Med Chem Lett. 2025 May 21;16(6):1066-1072. doi: 10.1021/acsmedchemlett.5c00105. eCollection 2025 Jun 12.
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.
帕西替尼是一种口服生物可利用的Janus激酶2大环抑制剂，已显示出治疗骨髓纤维化的疗效。由于合成大环类似物存在合成挑战，我们应用静电互补、3D场QSAR和自由能扰动方法对一组已知配体进行分析，以期开发一种优先排序方法，用于选择新的大环设计进行合成。研究表明了解配体的3D构象和灵活性很重要，这些效应会对预测的准确性产生重大影响。
