The dynamic properties of angiotensin II type 1 receptor inverse agonists in solution and in the receptor site

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 licens

The dynamic properties of angiotensin II type 1 receptor inverse agonists in solution and in the receptor site

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. © 2016 The Author

Leveraging NMR and X-ray data of the free ligands to build better drugs targeting angiotensin II Type 1 G-Protein coupled receptor

The angiotensin II type 1 receptor (AT1R) has been recently crystallized. A new era has emerged for the structure-based rational drug design and the synthesis of novel AT1R antagonists. In this critical review, the X-ray crystallographic data of commercially available AT1R antagonists in free form are analyzed and compared with the conformational analysis results obtained using a combination of NMR spectroscopy and Molecular Modeling. The same AT1R antagonists are docked and compared in terms of their interactions in their binding site using homology models and the crystallized AT1R receptor. Various aspects derived from these comparisons regarding rational drug design are outlined. © 2016 Bentham Science Publishers

Host-Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism

Renin−angiotensin aldosterone system inhibitors are for 25 a long time extensively used for the treatment of cardiovascular and renal 26 diseases. AT1 receptor blockers (ARBs or sartans) act as antihypertensive 27 drugs by blocking the octapeptide hormone Angiotensin II to stimulate 28 AT1 receptors. The antihypertensive drug candesartan (CAN) is the active 29 metabolite of candesartan cilexetil (Atacand, CC). Complexes of 30 candesartan and candesartan cilexetil with 2-hydroxylpropyl-β-cyclodextrin 31 (2-HP-β-CD) were characterized using high-resolution electrospray 32 ionization mass spectrometry and solid state 13C cross-polarization/ 33 magic angle spinning nuclear magnetic resonance (CP/MAS NMR) 34 spectroscopy. The 13C CP/MAS results showed broad peaks especially in 35 the aromatic region, thus confirming the strong interactions between 36 cyclodextrin and drugs. This experimental evidence was in accordance with molecular dynamics simulations and quantum mechanical calculations. The 37 synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN’s complexation, CAN exerts higher 38 antagonistic activity than CC. Therefore, a formulation of CC with 2-HP-β-CD is not indicated, while the formulation with CAN is promising and needs 39 further investigation. This intriguing result is justified by the binding free energy calculations, which predicted efficient CC binding to 2-HP-β-CD, and 40 thus, the molecule’s availability for release and action on the target is diminished. In contrast, CAN binding was not favored, and this may allow easy 41 release for the drug to exert its bioactivity