Cytisine, a natural product with high affinity for clinically relevant nicotinic acetylcholine receptors (nAChRs), is used as a smoking-cessation agent. The compound displays an excellent clinical profile and hence there is an interest in derivatives that may be further improved or find use in the treatment of other conditions. Here, the binding of a cytisine derivative modified by the addition of a 3-(hydroxypropyl) moiety (ligand 4) to Aplysia californica acetylcholine-binding protein (AcAChBP), a surrogate for nAChR orthosteric binding sites, was investigated. Isothermal titration calorimetry revealed that the favorable binding of cytisine and its derivative to AcAChBP is driven by the enthalpic contribution, which dominates an unfavorable entropic component. Although ligand 4 had a less unfavorable entropic contribution compared with cytisine, the affinity for AcAChBP was significantly diminished owing to the magnitude of the reduction in the enthalpic component. The high-resolution crystal structure of the AcAChBP-4 complex indicated close similarities in the protein-ligand interactions involving the parts of 4 common to cytisine. The point of difference, the 3-(hydroxypropyl) substituent, appears to influence the conformation of the Met133 side chain and helps to form an ordered solvent structure at the edge of the orthosteric binding site.

中文翻译：

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来自加州海兔的 C(9)-金雀花氨酸衍生物结合乙酰胆碱结合蛋白的热力学特征和分子相互作用。

金雀花碱是一种对临床相关烟碱乙酰胆碱受体 (nAChR) 具有高亲和力的天然产物，被用作戒烟剂。该化合物表现出优异的临床特征，因此人们对可以进一步改进或用于治疗其他病症的衍生物感兴趣。在此，研究了通过添加 3-（羟丙基）部分（配体 4）修饰的金雀花碱衍生物与海兔乙酰胆碱结合蛋白（AcAChBP）（nAChR 正构结合位点的替代物）的结合。等温滴定量热法表明，金雀花碱及其衍生物与 AcAChBP 的有利结合是由焓贡献驱动的，该贡献主导了不利的熵分量。尽管与金雀花碱相比，配体 4 的不利熵贡献较小，但由于焓成分减少的幅度，对 AcAChBP 的亲和力显着降低。AcAChBP-4 复合物的高分辨率晶体结构表明，涉及 4 与金雀花碱共有部分的蛋白质-配体相互作用非常相似。不同点是 3-（羟丙基）取代基，似乎会影响 Met133 侧链的构象，并有助于在正位结合位点边缘形成有序的溶剂结构。