Binding affinity modification

Anatoxin-a is the most potent and most stereospecific nicotinic acetylcholine receptor agonist thus far identified. It is also highly selective for nicotinic receptors over muscarinic receptors. The molecular parameters which influence the binding affinity, channel activation, channel blockade, and receptor desensitization are being studied. Modifications of the carbonyl and amine moieties can reduce or nearly eliminate the receptor agonist potency of the compounds and also determine the channel blocking characteristics. 

Recent advances in mass spectrometry (MS) technology have provided researchers with an unparalleled ability to identify the types and patterns of secondary biochemical modifications found on proteins in living cells. Matrix-assisted laser desorption/ionization-MS (MALDI-MS) analyses have shown, for example, that HMGA proteins in vivo are simultaneously subject to complex patterns of phosphorylation, acetylation and methylation and that, within the same cell type, different isoforms of these proteins can exhibit quite different modification patterns [33]. Furthermore, these in vivo modifications have been demonstrated to markedly alter the binding affinity of HMGA proteins for both DNA and chromatin substrates in vitro [33]. Nevertheless, due to their number and complexity, it has been difficult to determine the actual biological function(s) played by these biochemical modifications in living cells. 

The relative tubulin binding properties of a collection of bisindole alkaloids reflect the importance of combined modifications at C-4 and N-1 (Table XII) (94). Replacement of the vinblastine C-4 hydroxyl with hydrogen results in reduction in tubulin affinity by over 50%. However, when this substitution is combined with inversion of configuration at C-4, the tubulin binding affinity is increased by 84%. Replacement of the N-1 methyl with formyl increases tubulin affinity an additional 37%. The... 

Dimers of kanamycin and neomycin have also been synthesized (Figure 4.14). The 5"-OH and 6 -OH are the only primary hydroxy groups on neomycin and kanamycin, respectively, and often served as the point of modification. The studies in these articles, however, focus on the binding affinities of these kanamycin and neomycin dimers toward various RNA sequences of biological interest. 

---