title: Targeting metalloproteins by fragment-based lead discovery.
abstract: It has been estimated that nearly one-third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal-binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment-based drug discovery approach using a metal-targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target's metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Sherida
authors.initials: S
authors.lastname: Johnson
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Farina
authors.forename: Angela
authors.initials: A
authors.lastname: Purves
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Li-Hsing
authors.initials: LH
authors.lastname: Chen
authors.forename: Sergey
authors.initials: S
authors.lastname: Shiryaev
authors.forename: Ziming
authors.initials: Z
authors.lastname: Zhang
authors.forename: Irina
authors.initials: I
authors.lastname: Rodionova
authors.forename: Arpita
authors.initials: A
authors.lastname: Agrawal
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Andrei
authors.initials: A
authors.lastname: Osterman
authors.forename: Alex
authors.initials: A
authors.lastname: Strongin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry*; D016503:Drug Delivery Systems; D020128:Inhibitory Concentration 50; D008667:Metalloproteins / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry
chemical_list: D056831:Coordination Complexes; D008667:Metalloproteins; D010446:Peptide Fragments; D054852:Small Molecule Libraries; D015032:Zinc