{"title":"Application of Free Energy Perturbation (FEP) Methodology for Predicting the Binding Affinity of Macrocyclic JAK2 Inhibitor Analogues of Pacritinib.","authors":"Natércia F Braz, Martin J Slater, Stuart Lang","doi":"10.1021/acsmedchemlett.5c00105","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1066-1072"},"PeriodicalIF":3.5000,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169459/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.5c00105","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/12 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
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.
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.