With the use of an NMR-based method, potent (IC50 <
25 nM) nonpeptide inhibitors of the matrix
metalloproteinase stromelysin (MMP-3) were discovered. The method,
called SAR by NMR (for structure−activity
relationships by nuclear magnetic resonance), involves the
identification, optimization, and linking of compounds
that bind to proximal sites on a protein. Using this technique,
two ligands that bind weakly to stromelysin
(acetohydroxamic acid, K
D = 17 mM;
3-(cyanomethyl)-4‘-hydroxybiphenyl, K
D = 0.02
mM) were identified. On
the basis of NMR-derived structural information, the two fragments were
connected to produce a 15 nM inhibitor of
this enzyme. This compound was rapidly discovered (less than 6
months) and required only a minimal amount of
chemical synthesis. These studies indicate that the SAR by NMR
method can be effectively applied to enzymes to
yield potent lead inhibitorsan important part of the drug discovery
process.
A series of 3'-, 4'-, and 5'-substituted nicotine analogs have been synthesized and evaluated as ligands of the neuronal nicotinic acetylcholine receptor. The compounds prepared were found to have binding affinities ranging from 4 to 3500 nM. The results indicate that only a small substituent or functionality is well tolerated at the C4' position of nicotine and that binding affinity is affected by both steric and electronic properties of the substituent. On the other hand, the C3' and C5' positions seem to be the more sensitive toward bulky substituents. The best compound, 4'-methylnicotine, is nearly equipotent to nicotine. It possesses the most favorable binding affinity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.