Unique "delta lock" structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor |
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| Authors: | Ohno Kazuki Amano Yasushi Kakuta Hirotoshi Niimi Tatsuya Takakura Shoji Orita Masaya Miyata Keiji Sakashita Hitoshi Takeuchi Makoto Komuro Issei Higaki Jitsuo Horiuchi Masatsugu Kim-Mitsuyama Shokei Mori Yutaka Morishita Ryuichi Yamagishi Sho-ichi |
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| Affiliation: | aDrug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan;bDepartment of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan;cDepartment of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Toon, Japan;dDepartment of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Toon, Japan;eDepartment of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan;fDivision of Diabetes and Endocrinology, Department of Internal Medicine, Jikei University Daisan Hospital, Komae, Japan;gDepartment of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan;hDepartment of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan |
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| Abstract: | 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. |
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| Keywords: | Angiotensin II type 1 receptor blockers Docking model Hypertension Telmisartan |
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