Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor
Molecular Modeling Evaluation of the Enantiomers of a Novel Adenylyl Cyclase 2 Inhibitor
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DOI：
10.1021/acs.jcim.6b00454
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发表时间：
2017-02-01
影响因子：
5.6
通讯作者：
Lill, Markus A.
中科院分区：
文献类型：
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作者：
Rana, Neha;Conley, Jason M.;Lill, Markus A.
腺苷酸环化酶 2 (AC2) 是腺苷酸环化酶的九种膜结合亚型之一，可将 ATP 转化为重要的第二信使分子环 AMP (cAMP)。 AC2 的上调与胰腺癌和小肠神经内分泌肿瘤 (NETS) 等癌症有关。腺苷酸环化酶的各种异构体的结构具有高度同源性，这对有效的 AC2 异构体选择性调节剂的药物发现工作提出了重大挑战。在之前的一项研究中，筛选发现了一种潜在的 AC2 异构体选择性非竞争性抑制剂 SKF83566。本研究利用分子模型探讨SKF83566抑制AC2的模式，并研究SKF83566的活性对映体。基于犬ACS-Cla和大鼠AC2-C2a模板构建hAC2同源模型。通过这些模型，灵活对接、分子动力学模拟和使用 MM/GBSA 方法的自由能计算相结合，提出了一种变构机制，其中 (S)-SKF83566 与 ATP 附近的变构位点结合，并改变 ATP 结合位点的蛋白质构象，可能阻止 ATP 的腺苷部分形成拱形形状以形成 cAMP。 (S)-SKF83566 对映体的预测结合偏好和预测自由能与实验数据一致。
Adenylyl cyclase 2 (AC2) is one of nine membrane-bound isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important second messenger molecule. Upregulation of AC2 is linked to cancers like pancreatic and small intestinal neuroendocrine tumors (NETS). The structures of the various isoforms of adenylyl cyclases are highly homologous, posing a significant challenge to drug discovery efforts for an effective, isoform-selective modulator of AC2. In a previous study, a screen identified a potential isoform-selective and noncompetitive inhibitor of AC2, SKF83566. In the present study, molecular modeling is used to explore the mode of inhibition of AC2 by SKF83566 and to investigate the active enantiomer of SKF83566. Homology models of hAC2 were built based on canine ACS-Cla and rat AC2-C2a templates. With these models, a combination of flexible docking, molecular dynamics simulations, and free energy calculations using the MM/GBSA methodology suggested an allosteric mechanism in which (S)-SKF83566 binds-to an allosteric site near ATP and alters the protein conformation of the ATP binding site, potentially preventing the adenosine moiety of ATP from forming an archlike shape to form cAMP. The predicted binding preference for the (S)-SKF83566 enantiomer and the predicted free energy are consistent with the experimental data.