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

IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL
ACS Medicinal Chemistry Letters Pub Date : 2025-05-21 eCollection Date: 2025-06-12 DOI:10.1021/acsmedchemlett.5c00105
Natércia F Braz, Martin J Slater, Stuart Lang
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引用次数: 0

Abstract

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.

应用自由能摄动(FEP)方法预测Pacritinib大环JAK2抑制剂类似物的结合亲和力。
Pacritinib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。由于与合成大环类似物相关的合成挑战,我们应用静电互补,3d场QSAR和自由能摄动方法对一组已知配体进行分析,以期开发一种优先选择合成新大环设计的方法。理解配体的三维构象和灵活性的重要性被证明,这些影响对预测的准确性有重要的影响。
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来源期刊
ACS Medicinal Chemistry Letters
ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-
CiteScore
7.30
自引率
2.40%
发文量
328
审稿时长
1 months
期刊介绍: ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.
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