Leveraging NMR and X-ray Data of the Free Ligands to Build Better Drugs Targeting Angiotensin II Type 1 G-Protein Coupled Receptor

Abstract

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.

Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction

“…55,56,59–61 Binding of AngII involves ~17 AT 1 R residues forming ionic, H-bond, van der Waals, and π − π stacking interactions (Figure 3B). The conformation of bound AngII observed in our MDS is similar to NMR, 62 flexible docking, 38 or modeling studies. 35 Superimposition of AngII and Olmesartan indicates overlap of their aromatic−acidic pharmacophore groups surrounded by shared residues, Tyr35 3.91 , Trp84 2.60 , Tyr87 2.63 , Lys199 5.42 , Arg167 ECL2 , Ile288 7.39 , and Tyr292 7.43 which validate competitive antagonism of AngII and ARBs (Figure S5).…”

The non‐biphenyl‐tetrazole angiotensin AT1 receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT1 receptor

“…The phenyl ring of eprosartan interacts with Val108 TM3 and Ser109 TM3 , as well as with Trp253 TM6 and Gln257 TM6 . The flexible side chain of Lys199 TM5 provides some conformational heterogeneity in AT 1 receptors (Kellici et al ., ,b); the amino group of this residue may reach the carboxyl group of eprosartan by forming salt bridges or may interact through water‐mediated interactions with the phenyl scaffold, which may explain the reduced binding affinity and inverse agonist activity of eprosartan upon mutation of Lys199 TM5 (Takezako et al ., ; Zhang et al ., ; Takezako et al ., ). The residues Tyr35 TM1 , Trp84 TM2 , Arg167 ECL2 , Met284 TM7 , Pro285 TM7 and Ile288 TM7 were not targeted in this study and are therefore not shown in Figure .…”

Δυναμικές Ιδιότητες Της Ολμεσαρτάνης Στο Διάλυμα Και Στο Ενεργό Κέντρο Του Υποδοχέα Τύπου 1 Της Αγγειοτασίνης ΙΙ

“…Structures of AT 1 R antagonists. Almost all of them contain three structural features: biphenyl tetrazole or acidic bioisostere (colored in blue), heterocyclic segment (colored in green) and small alkyl chain (colored in red) 55 .…”

“…As can be seen in Figure 1 The second extracellular loop in the two homology models (blue and red) and the crystal structure (green). C) Superimposition of the four key residues Arg167, Lys199, Tyr35 and Ile288 (in green are shown the residues in the crystal structure, in blue the residues in the rhodopsin homology model and in red the residues in the CXCR4 homology model) 55 .…”