Receptor bound conformation

It is important to note that most molecules are not rigid but may prefer a distrinct structure and the conformation of a molecule strongly depends on its specific environment. Hence, the crystal structure of a drug does not have to correspond to the receptor bound conformation. Also, a conformation in solution depends on the nature of the solvent and measuring conditions, and may change when the molecule is bound to the receptor [4]. In addition, different receptors or receptor subtypes can bind the same drug in different conformations. It is a general assumption and observation, but by far not a strict condition, that the conformation in aqueous solution is similar to the bound conformation and is a better representation of the bioactive conformation than an X-ray structure of the isolated molecule in the crystalline state. 

Figure 2 Spatial overlap of low energy conformers of H-Hat-D-O rn-Aic-Glu-NH2 (heavy lines) with proposed models of the p-receptor-bound conformation (light lines) based on conformational analysis of H-Tyr-D-0 rn-Phe-As p-NH2 [24] (left panel) and H-Tyr-Pro-Phe(NMe)-D-Pro-NH2 (PL017) [29] (right panel). 

This model of the receptor-bound conformation of TIP is characterized by a clustered configuration of the three aromatic moieties with the Phe3 aromatic ring sandwiched between the Tyr1 and Tic2 aromatic rings. 

Wilkes BC, Schiller, PW. Comparative analysis of various proposed models of the receptor-bound conformation of TIP(P)-related opioid antagonists. Biopolymers (Peptide Sci) 1995 37 391-400. 

Wilkes BC, Nguyen TM-D, Weltrowska G, Carpenter KA, Lemieux C, Chung NN, Schiller PW. The receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-OH related -opioid antagonists contains all trans peptide bonds. J Peptide Res 1998 51 386-394. 

Figure 4.8 Erythropoietin. Source Cheetham JC, Smith DM, Aoki KH, et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation, Nature Structural Biology 5 861-866 (1998).)...

Fig. 1.3 Analysis of TRH (a) analogs by the active-analog approach by Font and Marshall led to a proposal for the receptor-bound conformation compatible with internal cyclization to generate polycyclic analogs (b).

Inhibitors of the angiotensin-converting enzyme (ACE) served as a test bed for the active-analog approach in which one tries to deduce the receptor-bound conformation... 

The relationship between the structure of a series of peptides derived from the adrenocorticotropic hormone ACTH, and the behavioural activity in an active avoidance behaviour test, has been studied over the past 10-20 years. The results obtained were quite different from those in which endocrine activity relationships were studied. From the outcome of a quantitative study on the structure--behavioural activity of the ACTH-related peptides, suggestions about the spatial interactions at the receptor site were made. This receptor-bound conformation differed from those suggested by solution experiments or found in crystal structures. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

D. F Veber, Synthesis of new peptides based on models of receptor-bound conformation. Psychopharmacol Ser, 1987.3 12-19. 

Knowledge of the receptor-bound conformation of a ligand is of great help in drug design. Constraints can then be introduced to encourage... 

It has been suggested that y-turns are present in the solution structures of several peptides, and furthermore implicated in their bioactive conformations 101 including brady-kinin, 111 substance P,1121 cyclic somatostatin analogues, 131 cyclolinopeptide, 141 and the 6-opioid receptor bound conformation of enkephalin. 151 Yet, despite the fact that y-tums are frequently hypothesized to represent important features of secondary structure 161 based upon computational,1171 IR absorption,1181 NMR spectroscopic,119 201 and X-ray diffraction crystallographic determinations,1211 verification of the role of this predicted secondary structural element remains a difficult, but nonetheless critical step. 

Since the orientation of the Phe4 phenyl group in the delta receptor-bound conformation of enkephalins was not known, the obvious strategy was to obtain series of compounds that were altered in their orientation of... 

Figure 1 (Left) Model of the receptor-bound conformation of TIP containing all-trans peptide bonds (heavy lines) in spatial overlap with naltrindole (light lines). (Right) Model of the receptor bound conformation of H-Tyr-Tic-NH2 containing a cis peptide bond (heavy lines) in spatial overlap with naltrindole (light lines). In both cases the N-terminal amino group and the Tyr1 and Tic2 aromatic rings of the peptide are superimposed on the corresponding pharmacophoric moieties in the alkaloid structure.

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