Bhuiyan Mohiuddin Ahmed, Ishiguro Masaji, Hossain Murad, Nakamura Takashi, Ozaki Masanobu, Miura Shin-Ichiro, Nagatomo Takafumi
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akihaku, Niigata-shi 956-8603, Japan.
Life Sci. 2009 Jul 17;85(3-4):136-40. doi: 10.1016/j.lfs.2009.05.001. Epub 2009 May 14.
This study was designed to examine the importance of interaction in the binding of selective angiotensin II receptor antagonists to angiotensin II type 1 receptor using molecular modeling. The AT(1) antagonists used in this study were valsartan, candesartan and losartan.
AT(1) receptor structural model was constructed by homology modeling using structural models of rhodopsin photointermediates. Through molecular modeling, possible binding sites for these drugs were suggested to lie between transmembrane domains (TM) 3, 5, and 6 of AT(1) receptor.
The carboxylic acid group and tetrazole ring of valsartan possibly interact with Lys199 of TM5 and Ser109 of TM3 and Asn295 of TM7 of AT(1) receptor, respectively. In candesartan, carboxylic group, tetrazole ring, and ethoxy group oxygen possibly interact with Lys199 of TM5, Ser109 of TM3 and Asn295 of TM7 and Gln257 of TM6, respectively. In losartan, tetrazole ring and hydroxymethyl group possibly interact with Asn295 of TM7 and Ser109 of TM3, respectively.
The results of the present study suggested that candesartan interacts at a higher number of binding sites compared to valsartan whereas losartan has a lower number of binding sites with the amino acid residues of the AT(1) receptor. These findings are consistent with the data of the radioligand-binding studies of the antagonists with the AT(1) receptor.
本研究旨在利用分子建模研究选择性血管紧张素II受体拮抗剂与1型血管紧张素II受体结合中相互作用的重要性。本研究中使用的AT(1)拮抗剂为缬沙坦、坎地沙坦和氯沙坦。
通过使用视紫红质光中间体的结构模型进行同源建模构建AT(1)受体结构模型。通过分子建模，提示这些药物的可能结合位点位于AT(1)受体的跨膜结构域（TM）3、5和6之间。
缬沙坦的羧酸基团和四氮唑环可能分别与AT(1)受体TM5的Lys199、TM3的Ser109和TM7的Asn295相互作用。在坎地沙坦中，羧基、四氮唑环和乙氧基氧可能分别与TM5的Lys199、TM3的Ser109、TM7的Asn295和TM6的Gln257相互作用。在氯沙坦中，四氮唑环和羟甲基可能分别与TM7的Asn295和TM3的Ser109相互作用。
本研究结果提示，与缬沙坦相比，坎地沙坦与更多的结合位点相互作用，而氯沙坦与AT(1)受体氨基酸残基的结合位点数量较少。这些发现与拮抗剂与AT(1)受体的放射性配体结合研究数据一致。
