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首页> 外文期刊>RSC Advances >Halogen bonding enhances activity in a series of dual 5-HT6/D2 ligands designed in a hybrid bioisostere generation/virtual screening protocol
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Halogen bonding enhances activity in a series of dual 5-HT6/D2 ligands designed in a hybrid bioisostere generation/virtual screening protocol

机译：卤素键合增强了在杂交生物辐射生成/虚拟筛选协议中设计的一系列双5-HT6 / D2配体中的活性

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摘要

A novel hybrid bioisostere generation/virtual screening method combined with narrowing of chemical space through similarity to compounds that are active at the second target was successfully applied for the development of structurally new dual 5-HT _(6) /D _(2) receptor ligands. Consequently, a series of derivatives of the found hit 1d ( N -[2-(dimethylamino)ethyl]- N -(2-phenylethyl)aniline) was synthesized. The most active 5-HT _(6) /D _(2) ligands also showed affinity for 5-HT _(7) R and 5-HT _(2A) R. The para -chloroaniline derivative was identified as a potent dual 5-HT _(6) /5-HT _(7) receptor antagonist ( K _(i) = 24 nM and K _(b) = 30 nM, K _(i) = 4 nM and K _(b) = 1.4 nM, respectively). In the case of halogen-containing compounds, interesting structure–activity relationships were observed at 5-HT _(6) , D _(2) and 5-HT _(7) receptors, and the ligand–receptor complexes were subsequently examined using a molecular modelling approach that combined quantum-polarized ligand docking (QPLD) and Molecular-Mechanics-Generalized-Born/Surface Area (MM/GBSA) free-energy calculation, which permitted the identification of putative halogen binding pockets.
机译：一种新的混合生物辐射生成/虚拟筛选方法通过与第二靶标在第二靶标的化合物的相似性结合化学空间的缩小，用于在结构新的双5-HT _（6）/ d _（2）受体的开发中配体。因此，合成了发现麦芽1D（N - [2-（二甲基氨基）乙基] - N - （2-苯基乙基）苯胺）的一系列衍生物。最活跃的5-HT _（6）/ d _（2）配体也显示了对5-HT _（7）R和5-HT _（2A）R的亲和力。鉴定β-氯苯胺衍生物被鉴定为有效的双重5-HT _（6）/ 5-HT _（7）受体拮抗剂（k _（i）= 24nm和k _（b）= 30nm，k _（i）= 4nm和k _（b）分别= 1.4 nm）。在含卤素的化合物的情况下，在5-HT _（6），D _（2）和5-HT _（7）受体中观察有趣的结构 - 活性关系，随后使用配体 - 受体复合物使用一种分子建模方法，即组合量子偏振配体对接（QPLD）和分子 - 机械通用出生/表面积（MM / GBSA）自由能计算，这允许识别推定的卤素结合袋。

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