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首页> 外文期刊>RSC Advances >Halogen bonding enhances activity in a series of dual 5-HT6/D-2 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/D-2 ligands designed in a hybrid bioisostere generation/virtual screening protocol

机译：卤素键合增强了一系列双5-HT6 / D-2配体的活性，该配体设计在混合生物辐射生成/虚拟筛选协议中

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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-HT6/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-HT6/D-2 ligands also showed affinity for 5-HT7R and 5-HT2AR. The para-chloroaniline derivative was identified as a potent dual 5-HT6/5-HT7 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-HT6, D-2 and 5-HT7 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：一种新型的混合生物辐射产生/虚拟筛选方法通过与第二靶标的化合物的相似性结合化学空间的缩小，以应用于结构新的双5-HT6 / D-2受体配体的发展。因此，合成了发现的麦芽发现1D的一系列衍生物（N- [2-（二甲基氨基）乙基] -N-（2-苯基乙基）苯胺）。最活跃的5-HT6 / D-2配体也显示了对5-HT7R和5-HT2AR的亲和力。对氯苯胺衍生物被鉴定为有效的双5-HT6 / 5-HT7受体拮抗剂（K-I = 24nm，K-B = 30nm，K-1分别分别）分别为k-i = 4nm和k-b = 1.4nm）。在含卤素化合物的情况下，在5-HT6，D-2和5-HT7受体中观察有趣的结构 - 活性关系，随后使用组合量子偏振配体的分子建模方法检查配体 - 受体络合物对接（QPLD）和分子 - 力学 - 广义出生/表面积（MM / GBSA）自由能计算，其允许识别推定的卤素结合口袋。

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  • 来源
    《RSC Advances》 |2016年第60期|共8页
  • 作者

    Staron Jakub; Warszycki Dawid; Kurczab Rafal; Satala Grzegorz; Bugno Ryszard; Hogendorf Adam; Bojarski Andrzej J.;

  • 作者单位

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

    Polish Acad Sci Inst Pharmacol Dept Med Chem 12 Smetna St PL-31343 Krakow Poland;

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  • 正文语种 eng
  • 中图分类 化学;
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