A nuclear magnetic resonance (NMR)-based method is described in which
small organic molecules that bind to proximal subsites of a protein ar
e identified, optimized, and linked together to produce high-affinity
ligands. The approach is called ''SAR by NMR'' because structure-activ
ity relationships (SAR) are obtained from NMR. With this technique, co
mpounds with nanomolar affinities for the FK506 binding protein were r
apidly discovered by tethering two ligands with micromolar affinities.
The method reduces the amount of chemical synthesis and time required
for the discovery of high-affinity ligands and appears particularly u
seful in target-directed drug research.