组胺H1-receptor拮抗剂绑定网站。基于立体选择pharmacophoric模型(半)刚性H1-antagonists受体和包括一个已知的互动网站。

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怪兽Laak, Venhorst J, Donne-Op窝负责人通用,Timmerman H

组胺H1-receptor拮抗剂绑定网站。基于立体选择pharmacophoric模型(半)刚性H1-antagonists受体和包括一个已知的互动网站。

J地中海化学。1995年8月18日,38 (17):3351 - 60。

PubMed ID

7650688 (在PubMed

]

文摘

新H1-antagonist pharmacophoric模型结合位点是派生的,一个简单的原子,原子匹配的化合物是不够的;在这个模型中,从受体需要包括交互残留。获得这个模型中,几个(半)的生物活性构象刚性古典组胺H1-receptor拮抗剂进行了调查(赛庚啶、phenindamine曲普立啶,epinastine, mequitazine, IBF28145,和mianserine)。一般来说,这些抗组胺药包含两个芳香环和一个基本的氮原子。先前派生pharmacophoric模型与氮固定位置相对于两个芳香环现在发现不适合描述H1-antagonist结合位点。描述一种程序允许显著自由的位置基本组胺H1-antagonist的氮。访问的区域基本氮是局限于该地区访问其反离子组胺H1-receptor,即。Asp116羧酸盐集团。基本假定氮离子氢键形成一个与这个天冬氨酸C Cα-和β碳固定的蛋白质骨架。通过氢键,酸性质子的拮抗剂的方向考虑。在这些计算程序中,一个天冬氨酸是耦合的基本氮每个H1-antagonist考虑; the carboxylate group is connected to the positively charged nitrogen via geometric H-bonding restraints obtained from a thorough database search (CSD). Also to the basic nitrogen of the pharmacophore is coupled an aspartic acid (to yield our new template). In order to derive a model for the H1-antagonist binding site, the aromatic ring systems of the antagonists and template are matched according to a previously described procedure. Subsequently, the C alpha- and C beta-carbons of the aspartic acid coupled to the H1-antagonists are matched with those of the template in a procedure which allows the antagonist and the carboxylate group to adapt their conformation (and also their relative position) in order to optimize the overlap with the template. A six-point pharmacophoric model is derived which has stereoselective features and is furthermore able to distinguish between the so-called "cis"- and "trans"-rings mentioned in many (Q)SAR studies on H1-antagonists. Due to its stereoselectivity, the model is able to designate the absolute bioactive configuration of antihistamines such as phenindamine (S), epinastine (S), and IBF28145 (R). A further merit of this study is that a model is obtained which includes an amino acid from the receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

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药物靶点

药物	目标	类	生物	药理作用	行动
Mequitazine	组胺H1受体	蛋白质	人类	是的	拮抗剂	细节
Phenindamine	组胺H1受体	蛋白质	人类	是的	拮抗剂	细节