The binding of C-4-halogenated 1-(4-X-2,5-dimethoxyphenyl)-2-aminopropane (DOX) serotonin agonist psychedelics at all three 5-HT₂ receptor subtypes is up to two orders of magnitude stronger for X = Cl, Br, or I (but not F) than when C-4 bears a hydrogen atom and more than expected from their hydrophobicities. Our docking and molecular dynamics simulations agree with the fact that increasing the polarizability of halogens results in halogen–oxygen distances to specific backbone C═O groups, and C–X···O angles, in ranges expected for halogen bonds (XBs), which could contribute to the high affinities observed. Good linear correlations are found for each receptor type, indicating that the binding pocket–ligand affinity is enhanced as the XB interaction becomes stronger (i.e., I ≈ Br > Cl > F). It is also striking to note how the linear equations unveil that the receptor’s response on the strength of the XB interaction is quite similar among 5-HT_2A and 5-HT_2C, whereas the 5-HT_2B’s sensitivity is less. The calculated dipole polarizabilities in the binding pocket of the receptors reflect the experimental affinity values, indicating that less-polarizable and harder binding sites are more prone to XB formation.

中文翻译：

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5-HT2 受体亚家族和卤素键承诺

C-4-卤化 1-(4-X-2,5-二甲氧基苯基)-2-氨基丙烷 (DOX) 5-羟色胺激动剂迷幻剂与所有三种 5-HT _{2 的结合}X = Cl、Br 或 I（但不是 F）的受体亚型比 C-4 带有氢原子时强两个数量级，并且比它们的疏水性强两个数量级。我们的对接和分子动力学模拟同意这样一个事实，即增加卤素的极化率会导致卤素 - 氧与特定骨架 C=O 基团的距离和 C-X…O 角，在卤素键 (XBs) 的预期范围内，这可能有助于观察到的高亲和力。对于每种受体类型都发现了良好的线性相关性，表明随着 XB 相互作用的增强（即 I ≈ Br > Cl > F），结合口袋-配体的亲和力增强。同样引人注目的是线性方程如何揭示受体对 XB 相互作用强度的反应在 5-HT _2A之间非常相似和 5-HT _2C，而 5-HT _2B的灵敏度较低。受体结合口袋中计算出的偶极极化率反映了实验亲和力值，表明低极化和较硬的结合位点更容易形成 XB。