Jain Swati, Yadav Arpita
Chem Biol Drug Des. 2008 Mar;71(3):271-7. doi: 10.1111/j.1747-0285.2008.00634.x. Epub 2008 Jan 31.
In this study we report ab initio molecular orbital calculations on the natural hormone angiotensin II, which induces activity at AT1/AT2 receptor subtypes leading to vasoconstriction and subsequent hypertension, and AT2 antagonists. Pharmacophoric features of AT2 antagonists have been studied. A model of AT2 receptor has been made, and angiotensin II as well as antagonists has been systematically docked and their interactions with the receptor analyzed. Calculated ligand-receptor interaction energies have been correlated with experimentally observed biological potency data. Our studies indicate that antagonists retain sufficient interactions to block the receptor but may not be adequate to induce activity at the receptor. A poor antagonist is, therefore, proposed as a close mimic of angiotensin II in terms of interacting with the receptor. These studies further explore the mechanistic aspects of this important class of drugs.
在本研究中，我们报告了对天然激素血管紧张素II及AT2拮抗剂的从头算分子轨道计算。血管紧张素II可诱导AT1/AT2受体亚型产生活性，导致血管收缩及随后的高血压。我们研究了AT2拮抗剂的药效特征。构建了AT2受体模型，对血管紧张素II及拮抗剂进行了系统对接，并分析了它们与受体的相互作用。计算得到的配体-受体相互作用能已与实验观察到的生物活性数据相关联。我们的研究表明，拮抗剂保留了足够的相互作用以阻断受体，但可能不足以在受体上诱导活性。因此，提出一种低效拮抗剂在与受体相互作用方面可作为血管紧张素II的紧密模拟物。这些研究进一步探索了这类重要药物的作用机制。
