title: Systems-based design of bi-ligand inhibitors of oxidoreductases: filling the chemical proteomic toolbox.
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.
authors.affiliation: Triad Therapeutics, Inc, 9381 Judicial Drive, San Diego, CA 92121, USA. daniel.sem@marquette.edu
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Sem
authors.forename: Bonnie
authors.initials: B
authors.lastname: Bertolaet
authors.forename: Brian
authors.initials: B
authors.lastname: Baker
authors.forename: Edcon
authors.initials: E
authors.lastname: Chang
authors.forename: Aurora D
authors.initials: AD
authors.lastname: Costache
authors.forename: Stephen
authors.initials: S
authors.lastname: Coutts
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.forename: Mark
authors.initials: M
authors.lastname: Hansen
authors.forename: Victor
authors.initials: V
authors.lastname: Hong
authors.forename: Xuemei
authors.initials: X
authors.lastname: Huang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Jack
authors.forename: Richard
authors.initials: R
authors.lastname: Kho
authors.forename: Henk
authors.initials: H
authors.lastname: Lang
authors.forename: Chen-Ting
authors.initials: CT
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Meininger
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.forename: Hugo
authors.initials: H
authors.lastname: Villar
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D010088:Oxidoreductases; D009247:NADH, NADPH Oxidoreductases