| Summary: | In this article, the conformational properties of olmesartan and its methylated analogue were charted using a combination of NMR spectroscopy and molecular modeling. For the molecular docking experiments three different forms of angiotensin II type 1 receptor (AT1R) have been used: (a) crystal structure; (b) homology model based on CXCR4 and (c) homology model based on rhodopsin. The aim of this study was to possibly explain the differences between the experimental findings derived from mutagenesis studies on this receptor and the crystal structure of the AT1R-olmesartan complex. Molecular Dynamics (MD) experiments were performed to illustrate the stability of the AT1R-inverse agonist complex and the most prominent interactions during the simulated trajectory. The obtained results showed that olmesartan and its methyl ether exert similar interactions with critical residues justifying their almost identical in vitro activity. However, the docking and MD experiments failed to justify the mutation findings in a satisfactory matter, indicating that the real system is more complex and crystal structure or homology models of AT1R receptors cannot simulate it sufficiently. Various conformations of olmesartan and olmesartan methyl ether were simulated to provide chemical shifts. These are compared with the experimental NMR results. Useful information regarding the putative bioactive conformations of olmesartan and its methylated analogue has been obtained. Finally, comparative data regarding the binding poses and energies of olmesartan, olmesartan methyl ether and three derivative compounds of olmesartan (R239470, R781253, and R794847) were acquired using Prime/MM-GBSA calculations. Keywords: Angiotensin II type 1 receptor, Bioactive conformations, Olmesartan, NMR, Molecular dynamics, Induced fit docking
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