Analogs conformational property

Warshel, Levitt, and Lifson derived a partially optimised consistent force field for amides and lactams (25). It is composed of an alkane part and an amide-part. The former was taken over from analogous earlier calculations for saturated hydrocarbons (17). The potential constants of the amide-part were optimised with the help of a large number of experimental frequencies (taken from TV-methylform amide, acetamide, iV-methylacetamide, and several deuterated species) as well as experimental geometry data for 7V-methylacet-amide. The resulting force field was used for the calculation of vibrational and conformational properties of 2-pyrrolidone, 2-piperidone and e-caprolactam. 

We now turn to several examples where these techniques have been applied to peptide hormones, and show how we can study the conformational properties, including conformational minima and fluctuations, dynamics, and energetics of these molecules, and how these properties can in turn be used to design analogs. 

The conformational properties of such eight-membered ring molecules have been reviewed fairly recently (74MI51900). Cyclooctane is the archetypical molecule in this class, and the heterocyclic analogs, such as the azocanes, oxocanes and thiocanes, as well as carbocyclic derivatives, such as cyclooctanone, all have closely related conformational features and a brief overview of their conformations will now be given. 

The tetrahydrodibenzo[6,/][l,4]diazocines (458) and the tetrahydrodibenzo[6,/]-[l,5]diazocines (459), which have two nitrogens in the heterocyclic ring, as well as their sulfur analogs (460) and (461) show conformational properties similar to those of the monoaza compound (456). Typical data are included in Table 3. The assignments of conformations and transition states for these dibenzo derivatives are supported by force-field calculations and by detailed dynamic NMR measurements <73JCS(Pl)205>. 

The conformational properties of aromatic heterocycles are related to those of phenyl rings but with the added perturbations due to heteroatoms. We have carried out a systematic study of what we called aromatic propellenes, the heterocyclic analogs of hexaphenylbenzene (13) [27, 28], which possess interesting conformational [29] and metal complexing properties (14) [30],... 

To characterize protein-ligand interactions by F NMR, the ligand or the protein can be labeled with fluorine to produce spectra without overwhelming complexity. Proteins expressed in E.coli and tissue culture have been labeled with fluorine by biosynthetic incorporation of fluoro analogs of tryptophan, phenylalanine and tyrosine. Conformational properties of receptor... 

QSAR theories are convenient for the design of new analogs of a known active compound but these theories are not always able to go beyond the chemical frame of the particular family studied. Considering structure-activity studies in the light of the three dimensional specificity of molecular interactions between drugs and receptors, conformational properties appear to be essential. 

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