DISCOVERING HIGH-AFFINITY LIGANDS FOR PROTEINS - SAR BY NMR

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.