Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Biochem Biophys Res Commun. 2011 Jan 7;404(1):434-7. doi: 10.1016/j.bbrc.2010.11.139. Epub 2010 Dec 3.
Angiotensin II type 1 receptor (AT1 receptor) blockers (ARBs) are one of the most popular anti-hypertensive agents. Control of blood pressure (BP) by ARBs is now a therapeutic target for the organ protection in patients with hypertension. Recent meta-analysis demonstrated the possibility that telmisartan was the strongest ARB for the reduction of BP in patients with essential hypertension. However, which molecular interactions of telmisartan with the AT1 receptor could explain its strongest BP lowering activity remains unclear. To address the issue, we constructed models for the interaction between commonly used ARBs and AT1 receptor and compared the docking model of telmisartan with that of other ARBs. Telmisartan has a unique binding mode to the AT1 receptor due to its distal benzimidazole portion. This unique portion could explain the highest molecular lipophilicity, the greatest volume distribution and the strongest binding affinity of telmisartan to AT1 receptor. Furthermore, telmisartan was found to firmly bind to the AT1 receptor through the unique "delta lock" structure. Our present study suggests that due to its "delta lock" structure, telmisartan may be superior to other ARBs in halting cardiovascular disease in patients with hypertension.
血管紧张素 II 型 1 型受体（AT1 受体）阻滞剂（ARB）是最受欢迎的抗高血压药物之一。ARB 通过控制血压（BP），现已成为高血压患者器官保护的治疗靶点。最近的荟萃分析表明，替米沙坦可能是降低原发性高血压患者血压的最强 ARB。然而，替米沙坦与 AT1 受体的哪些分子相互作用可以解释其最强的降压活性仍不清楚。为了解决这个问题，我们构建了常用 ARB 与 AT1 受体相互作用的模型，并比较了替米沙坦与其他 ARB 的对接模型。替米沙坦因其远端苯并咪唑部分而具有独特的与 AT1 受体结合模式。这种独特的部分可以解释替米沙坦对 AT1 受体具有最高的分子亲脂性、最大的体积分布和最强的结合亲和力。此外，研究发现替米沙坦通过独特的“Delta 锁”结构与 AT1 受体牢固结合。本研究表明，由于其“Delta 锁”结构，替米沙坦可能优于其他 ARB，从而阻止高血压患者的心血管疾病进展。
