Document Type
Article
Language
eng
Publication Date
2-2004
Publisher
Elsevier
Source Publication
Chemistry & Biology
Source ISSN
1074-5521
Abstract
Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases.
Recommended Citation
Sem, Daniel S.; Bertolaet, Bonnie; Baker, Brian; Chang, Edcon; Costache, Aurora Demertrina; Coutts, Stephen; Dong, Qing; Hansen, Mark; Hong, Victor; Huang, Xuemei; Jack, Richard M.; Kho, Richard; Lang, Henk; Ma, Chen-Ting; Meininger, David; Pellacchia, Maurizio; Pierre, Fabrice; Villar, Hugo; and Yu, Lin, "Systems-Based Design of Bi-Ligand Inhibitors of Oxidoreductases: Filling the Chemical Proteomic Toolbox" (2004). Chemistry Faculty Research and Publications. 919.
https://epublications.marquette.edu/chem_fac/919
Comments
Accepted version. Chemistry & Biology, Vol. 11, (February, 2004): 185–194. DOI. © 2004 Elsevier B.V. Used with permission.