ARBs that are widely used in clinics share a common molecular scaffold consisting of biphenyl-tetrazol and imidazole groups that have AbMole Riociguat BAY 63-2521 slightly different structures. Recent clinical studies have demonstrated that not all ARBs have the same effects and some benefits conferred by ARBs may not be class effects, but rather molecule-specific effects. We and others previously indicated that each ARB has a unique mode of binding for AT1 receptor. We have AbMole Trihexyphenidyl HCl proposed that the molecule-specific effects may be due to small differences in the molecular structure of each ARB. While the crystal structures of GPCRs obtained from the rhodopsin, opsin, and beta1 and beta2 adrenergic receptor systems have recently been described, the crystal structure of AT1 receptor has not been elucidated. Although we and others analyzed 
the mode of binding of ARBs to AT1 receptor. These analyses considered different positions of the AT1 receptor using sitedirected mutagenesis and performed computational modeling using different GPCR crystal structures as templates and also different softwares which could account for the different modes of binding of ARBs to AT1 receptor observed. To resolve these problems, in this study we systematically analyzed the same critical positions of AT1 receptor, Tyr113, Tyr184, Lys199, His256 and Gln257, which may commonly bind to ARBs according to previous reports, using a mutagenesis study, and subsequently performed computational modeling of the binding mode between AT1 receptor and ARBs using human C-X-C chemokine receptor type 4 receptor as a new template and a single version of software. We confirmed here that the slightly different structures of ARBs are critical for unique modes of binding to AT1 receptor. Since telmisartan and irbesartan do not contain an imidazole ring with a carboxyl group, these ARBs should be considered separately from the other ARBs which do contain a carboxyl group. According to results of modeling, the benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr113 by the hydrophobic effect, such as van der Waals forces. In fact, the cyclopentyl group should move toward Tyr113 to slightly move the protein side chains, but because the chains are fixed in the docking studies, steric interference may occur and thus the correct original position cannot be obtained in the present modeling. 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. Influenza is an acute viral and highly contagious respiratory infection causing significant morbidity and mortality worldwide with public health implications. Two main types of influenza virus are responsible for recurrent epidemics in humans.