Conformational restriction small ligands

Conformational restriction is a very powerful method for probing the bioactive conformations of peptides. Small peptides have many flexible torsion angles so that enormous numbers of conformations are possible in solution. For example, a simple tripeptide such as thyrotropin-releasing hormone (TRH 7) (Fig. 15.4) with six flexible bonds could have over 65,000 possible conformations. The number of potential conformers for larger peptides is enormous, and some method is needed to exclude potential conformers. Modem biophysical methods, e.g., X-ray crystallography or isotope edited nuclear magnetic resonance (NMR), (33) can be used to characterize peptide-protein interactions for soluble proteins, but most biophysical methods cannot yet determine the conformation of a ligand bound to constitutive receptors, e.g., G-protein-coupled receptors (34, 35). 

In this example, computational methods and crystal structures of related small molecules both allow us to estimate a conformation for the ligand, which resembles the biologically active conformation at the receptor site. However, retinol is a rather hydrophobic and conformationally restricted molecule. It binds to the active site through many hydrophobic contacts which are not strongly directional. The only polar group (OH) is situated near the entrance of the binding pocket, thus interacting... 

The principle of conformational restriction was first applied to characterize the bioactive conformation of acetyl choline acting at the muscarinic and nicotinic receptors. Conformational restriction has been applied to many other small ligands (e.g. see reviews by Martin-Smith et al., Portogh-ese, Mutschler and Lambrecht, and Casy et but the work on acetylcholine analogs exemplifies the necessary ideas and techniques required to understand the general approach, as well as its strengths and limitations, when applied to small molecules. 

We wondered why NSCs proliferated exclusively on surfaces with EGF-His ligands anchored by coordination. We focused on two aspects in particular the conformational integrity of coordinated EGF-His and the stability of coordinate bonds at the interface. Conformational information was acquired with multiple internal reflection-infrared absorption spectroscopy (MIR-IRAS) [97]. The stability of coordinate bonds was assessed by culturing NSCs on a surface with a small region of EGF-His ligands anchored by coordination. This spatially restricted EGF-His anchoring enabled an intuitive exploration of EGF-His release under cell culture conditions. 

The ADP moiety is a very flexible structure and could assume a variety of conformations in the binding site. However, in practice there are only a small number of bound conformations that are actually observed. The architecture of the site, conserved by evolution, appears to restrict the conformations found. The approach described in Section 2 is to apply classification methods to the ligand conformations and then to hunt for structural and functional correlations derived from the site which are associated with the observed ligand conformations. 

Capsule-shaped Ir(l) and Rh(l) cationic complexes with a triphosphinocaltx[6]arene as a multidentate ligand were recently synthesized (Figure 33). These organometallic bis-caltxarene complexes showed dynamic behavior with size-selective molecular encapsulation, which was confirmed by variable-temperature P H NMR measurements in the presence of various molecules. X-ray crystal analysis showed that the calix[6]arene moiety adopted the same pinched-cone conformation as the non-coordinated caltxarene. Molecules such as CFlj,Cly or CICH2CH2CI are too small to fit the cavity of the iridium and rhodium bis-calixarene complexes and cannot restrict the dynamic behavior at 25 °C. On the contrary, molecules such as X2CHCHX2 (X = C1 or Br), benzene, toluene, o- or w-xylene just fit in the cavity and show the dynamic behavior. Finally, large molecules (p-xylene, cumene, mesitylene, etc.) could not enter the cavity. 

---