Structure Activity Relationship by NMR and by Computer: A Comparative Study
详细信息 查看全文
- 作者：Finton Sirockin ; Christian Sich ; Sabina Improta ; Michael Schaefer ; Vladimir Saudek ; Nicolas Froloff ; Martin Karplus ; and Annick Dejaegere
- 刊名：Journal of the American Chemical Society
- 出版年：2002
- 出版时间：September 18, 2002
- 年：2002
- 卷：124
- 期：37
- 页码：11073 - 11084
- 全文大小：852K
- 年卷期：v.124,no.37(September 18, 2002)
- ISSN：1520-5126
文摘
There has recently been considerable interest in using NMR spectroscopy to identify ligand bindingsites 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 ligandsthat bind to a particular target are identified in a first round of screening and subsequently linked togetherto 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 subsequentlyassembled from different groups that have favorable interactions with the macromolecular target. In thispaper, we compare experimental and computational results on a selected target (FKBP12). The bindingsites of three small ligands ((2S)1-acetylprolinemethylester, 1-formylpiperidine, 1-piperidinecarboxamide)in FKBP12 were identified independently by NMR and by computational methods. The subsequentcomparison of the experimental and computational data showed that the computational method identifiedand ranked favorably ligand positions that satisfy the experimental NOE constraints.