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Structure Activity Relationship by NMR and by Computer: A Comparative Study
journal contribution
posted on 2002-08-23, 00:00 authored by Finton Sirockin, Christian Sich, Sabina Improta, Michael Schaefer, Vladimir Saudek, Nicolas Froloff, Martin Karplus, Annick DejaegereThere 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.