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Abstract
While the molecular structures of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) are very similar, they are also slightly different. Although each ARB has been shown to exhibit a unique mode of binding to AT1 receptor, different positions of the AT1 receptor have been analyzed and computational modeling has been performed using different crystal structures for the receptor as a template and different kinds of software. Therefore, we systematically analyzed the critical positions of the AT1 receptor, Tyr113, Tyr184, Lys199, His256 and Gln257 using a mutagenesis study, and subsequently performed computational modeling of the binding of ARBs to AT1 receptor using CXCR4 receptor as a new template and a single version of software. The interactions between Tyr113 in the AT1 receptor and the hydroxyl group of olmesartan, between Lys199 and carboxyl or tetrazole groups, and between His256 or Gln257 and the tetrazole group were studied. The common structure, a tetrazole group, of most ARBs similarly bind to Lys199, His256 and Gln257 of AT1 receptor. Lys199 in the AT1 receptor binds to the carboxyl group of EXP3174, candesartan and azilsartan, whereas oxygen in the amidecarbonyl group of valsartan may bind to Lys199. The benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr113. On the other hand, the n-butyl group of irbesartan may bind to Tyr113. In conclusion, we confirmed that the slightly different structures of ARBs may be critical for binding to AT1 receptor and for the formation of unique modes of binding.
Highlights
Angiotensin II (Ang II) type 1 (AT1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily and contains 359 amino acids [1]
Similar to EXP3174, valsartan, candesartan and azilsartan showed a more than 10-fold loss of affinity in Y113A, K199A and Q257A mutant receptors compared to the AT1-WT receptor, which indicated that Tyr113, Lys199 and Gln257 in the AT1 receptor are involved in binding to the 4 ARBs which have a carboxyl group as a common chemical structure
We confirmed that the slightly different structures of ARBs are important for unique modes of binding to AT1 receptor using mutagenesis-guided docking to AT1 receptor model based on CXCR4 receptor [25] as a new template and a single version of software
Summary
Angiotensin II (Ang II) type 1 (AT1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily and contains 359 amino acids [1]. It has a widespread tissue distribution and mediates most known cardiovascular functions including vasoconstriction, cardiovascular hypertrophy and hyperplasia [2]. AT1 receptor blockers (ARBs, including EXP3174, which is an active metabolite of losartan, candesartan, eprosartan, valsartan, telmisartan, olmesartan, irbesartan, and azilsartan) have been developed and are available for clinical use worldwide. Basic and clinical studies have shown that ARBs are useful for preventing the development of cardiovascular disease [2].
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