Systems-based design of bi-ligand inhibitors of oxidoreductases: filling the chemical proteomic toolbox.
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.
Sem
Daniel S
DS
Triad Therapeutics, Inc, 9381 Judicial Drive, San Diego, CA 92121, USA. daniel.sem@marquette.edu
Bertolaet
Bonnie
B
Baker
Brian
B
Chang
Edcon
E
Costache
Aurora D
AD
Coutts
Stephen
S
Dong
Qing
Q
Hansen
Mark
M
Hong
Victor
V
Huang
Xuemei
X
Jack
Richard M
RM
Kho
Richard
R
Lang
Henk
H
Ma
Chen-Ting
CT
Meininger
David
D
Pellecchia
Maurizio
M
Pierre
Fabrice
F
Villar
Hugo
H
Yu
Lin
L
D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D015723:Gene Library; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D040901:Proteomics / Q000379:methods*; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D008024:Ligands; D010088:Oxidoreductases; D009247:NADH, NADPH Oxidoreductases