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 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.

[1]  G. Bodenhausen,et al.  Natural abundance nitrogen-15 NMR by enhanced heteronuclear spectroscopy , 1980 .

[2]  Mike Carson,et al.  Ribbon models of macromolecules , 1987 .

[3]  R F Standaert,et al.  Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex , 1991, Science.

[4]  Stuart L. Schreiber,et al.  Atomic Structure of the Rapamycin Human Immunophilin FKBP-12 Complex , 1991 .

[5]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.

[6]  R. Williams,et al.  Design and synthesis of novel FKBP inhibitors. , 1992, Journal of medicinal chemistry.

[7]  Wim G. J. Hol,et al.  In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach , 1992, J. Comput. Aided Mol. Des..

[8]  Paul A. Keifer,et al.  Pure absorption gradient enhanced heteronuclear single quantum correlation spectroscopy with improved sensitivity , 1992 .

[9]  M. Murcko,et al.  GroupBuild: a fragment-based method for de novo drug design. , 1993, Journal of medicinal chemistry.

[10]  A. Petros,et al.  Three-dimensional structure of the FK506 binding protein/ascomycin complex in solution by heteronuclear three- and four-dimensional NMR. , 1993, Biochemistry.

[11]  M Karplus,et al.  HOOK: A program for finding novel molecular architectures that satisfy the chemical and steric requirements of a macromolecule binding site , 1994, Proteins.

[12]  Jon Clardy,et al.  DESIGN, SYNTHESIS, AND KINETIC EVALUATION OF HIGH-AFFINITY FKBP LIGANDS AND THE X-RAY CRYSTAL-STRUCTURES OF THEIR COMPLEXES WITH FKBP12. , 1994 .

[13]  S. P. Fodor,et al.  Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries. , 1994, Journal of medicinal chemistry.

[14]  Karen N. Allen,et al.  An Experimental Approach to Mapping the Binding Surfaces of Crystalline Proteins , 1996 .