Binding of the Hemopressin Peptide to the Cannabinoid CB1 Receptor: Structural Insights
Binding of the Hemopressin Peptide to the Cannabinoid CB1 Receptor: Structural Insights
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DOI：
10.1021/bi1011833
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发表时间：
2010-12-14
期刊：
影响因子：
2.9
通讯作者：
D'Ursi, Anna Maria
中科院分区：
文献类型：
--
作者：
Scrima, Mario;Di Marino, Sara;D'Ursi, Anna Maria
加压素是一种衍生自血红蛋白α 1链的生物活性九肽，最近显示对大麻素CBI受体具有选择性拮抗剂活性[Heimann，A.美国，等人（2007）Proc.Natl. Acad. Sci. U.S.A.104，20588-20593]。CB 1受体拮抗剂因其在治疗肥胖、药物滥用和海洛因成瘾中的可能治疗用途而被广泛研究。特别是，已经合成了许多用作CB 1受体拮抗剂的化合物，并作为可能的抗肥胖药物进行了实验，但它们的治疗应用仍然因重要的副作用而复杂化。利用圆二色谱和核磁共振光谱，本工作报告的构象分析的加压素及其截短的，生物活性片段加压素（1-6）。通过分子对接计算研究了加压素和加压素（1-6）的结合模式。我们的构象数据表明，在加压素和加压素（1-6）的中心部分的规则转弯结构与受体的有效相互作用是至关重要的。分子对接计算的结果，表明最公认的CB 1药效团模型相比的相似性和差异，表明新的化学支架的设计新的CB 1拮抗剂先导化合物的可能性。
Hemopressin, a bioactive nonapeptide derived from the alpha 1 chain of hemoglobin, was recently shown to possess selective antagonist activity at the cannabinoid CBI receptor [Heimann, A. S., et al. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 20588-20593]. CB1 receptor antagonists have been extensively studied for their possible therapeutic use in the treatment of obesity, drug abuse, and heroin addiction. In particular, many compounds acting as CB1 receptor antagonists have been synthesized and subjected to experiments as possible anti-obesity drugs, but their therapeutic application is still complicated by important side effects. Using circular dichroism and nuclear magnetic resonance spectroscopy, this work reports the conformational analysis of hemopressin and its truncated, biologically active fragment hemopressin(1-6). The binding modes of both hemopressin and hemopressin(1-6) are investigated by molecular docking calculations. Our conformational data indicate that regular turn structures in the central portion of hemopressin and hemopressin(1-6) are critical for an effective interaction with the receptor. The results of molecular docking calculations, indicating similarities and differences in comparison to the most accepted CB1 pharmacophore model, suggest the possibility of new chemical scaffolds for the design of new CB1 antagonist lead compounds.