@article{2957212,
    title = "The dynamic properties of angiotensin II type 1 receptor inverse agonists in solution and in the receptor site",
    author = "T.F. Kellici, D. Ntountaniotis, G. Liapakis, A.G. Tzakos, T. Mavromoustakos,",
    journal = "Arabian Journal of Chemistry",
    year = "2019",
    volume = "12",
    number = "8",
    pages = "5062-5078",
    publisher = "Elsevier",
    issn = "1878-5352",
    keywords = "Angiotensin II type 1 receptor; Bioactive conformations; Olmesartan; NMR; Molecular dynamics; Induced fit docking",
    abstract = "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 AT1Rolmesartan 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.

 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is
an open access article under the CC BY-NC-ND license"
}