title: Discovering high-affinity ligands for proteins: SAR by NMR.
abstract: A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands. The approach is called "SAR by NMR" because structure-activity relationships (SAR) are obtained from NMR. With this technique, compounds with nanomolar affinities for the FK506 binding protein were rapidly 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 useful in target-directed drug research.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Shuker
authors.forename: P J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: R P
authors.initials: RP
authors.lastname: Meadows
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D000813:Anilides / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011506:Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins
chemical_list: D000813:Anilides; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D011506:Proteins; C034595:benzanilide; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus