title: Structure activity relationship by NMR and by computer: a comparative study.
abstract: There has recently been considerable interest in using NMR spectroscopy to identify ligand binding sites of macromolecules. In particular, a modular approach has been put forward by Fesik et al. (Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Science 1996, 274, 1531-1534) in which small ligands that bind to a particular target are identified in a first round of screening and subsequently linked together to form ligands of higher affinity. Similar strategies have also been proposed for in silico drug design, where the binding sites of small chemical groups are identified, and complete ligands are subsequently assembled from different groups that have favorable interactions with the macromolecular target. In this paper, we compare experimental and computational results on a selected target (FKBP12). The binding sites of three small ligands ((2S)1-acetylprolinemethylester, 1-formylpiperidine, 1-piperidinecarboxamide) in FKBP12 were identified independently by NMR and by computational methods. The subsequent comparison of the experimental and computational data showed that the computational method identified and ranked favorably ligand positions that satisfy the experimental NOE constraints.
authors.affiliation: Contribution from the Laboratoire de Biologie et Génomique Structurales, UMR 7104, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard S. Brant, FR-67400 Illkirch, France.
authors.forename: Finton
authors.initials: F
authors.lastname: Sirockin
authors.forename: Christian
authors.initials: C
authors.lastname: Sich
authors.forename: Sabina
authors.initials: S
authors.lastname: Improta
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.forename: Vladimir
authors.initials: V
authors.lastname: Saudek
authors.forename: Nicolas
authors.initials: N
authors.lastname: Froloff
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
authors.forename: Annick
authors.initials: A
authors.lastname: Dejaegere
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D013329:Structure-Activity Relationship; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D022061:Tacrolimus Binding Protein 1A