Unique "delta lock" structure of telmisartan is involved in its strongest binding affinity to angiotensin II type 1 receptor.
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.
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Japan.
Kazuki
K
Ohno
Yasushi
Y
Amano
Hirotoshi
H
Kakuta
Tatsuya
T
Niimi
Shoji
S
Takakura
Masaya
M
Orita
Keiji
K
Miyata
Hitoshi
H
Sakashita
Makoto
M
Takeuchi
Issei
I
Komuro
Jitsuo
J
Higaki
Masatsugu
M
Horiuchi
Shokei
S
Kim-Mitsuyama
Yutaka
Y
Mori
Ryuichi
R
Morishita
Sho-ichi
S
Yamagishi
D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology; D002417:Cattle; D018360:Crystallography, X-Ray; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D008958:Models, Molecular; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry*; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan