Abstract：
The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR-ARNT-DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS-B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.
摘要：
人类芳香烃受体（AhR），配体依赖性转录因子，在生物和病理生理事件的各种途径中起着关键作用。此位置AhR是致癌作用和抗肿瘤策略的有希望的靶标。在这项研究中，我们利用计算模型来筛选和鉴定FDA批准的药物与bHLH的α2和AhR的PAS-A结构域之间的变构位点结合，目的是抑制其典型途径的活性。我们的发现表明，尼洛替尼有效地适应变构口袋，并与关键残基F82，Y76和Y137形成相互作用。尼洛替尼的结合自由能值在顶部命中中最低,并且在整个(MD)模拟时间内在其口袋内保持稳定。尼洛替尼与F295和Q383结合并激活AhR时也具有实质性的相互作用。令人惊讶的是,在存在AhR激动剂的情况下，它不会影响AhR核易位；相反，它阻碍了功能性AhR-ARNT-DNA异源二聚体组装的形成，防止调节酶如CYP1A1的上调。重要的是,尼洛替尼对AhR具有双重影响，通过PAS-B结构域调节AhR活性,并作为非竞争性变构拮抗剂,能够在有效的AhR激动剂存在下阻断典型的AhR信号传导途径。这些发现为尼洛替尼的重新定位开辟了新的途径，超越了其目前在通过AhR介导的多种疾病中的应用。
