title: Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
abstract: Fragment-based lead design (FBLD) has been used to identify new metal-binding groups for metalloenzyme inhibitors. When screened at 1 mM, a chelator fragment library (CFL-1.1) of 96 compounds produced hit rates ranging from 29% to 43% for five matrix metalloproteases (MMPs), 24% for anthrax lethal factor (LF), 49% for 5-lipoxygenase (5-LO), and 60% for tyrosinase (TY). The ligand efficiencies (LE) of the fragment hits are excellent, in the range of 0.4-0.8 kcal/mol. The MMP enzymes all generally elicit the same chelators as hits from CFL-1.1; however, the chelator fragments that inhibit structurally unrelated metalloenzymes (LF, 5-LO, TY) vary considerably. To develop more advanced hits, one hit from CFL-1.1, 8-hydroxyquinoline, was elaborated at four different positions around the ring system to generate new fragments. 8-Hydroxyquinoline fragments substituted at either the 5- or 7-positions gave potent hits against MMP-2, with IC(50) values in the low micromolar range. The 8-hydroxyquinoline represents a promising new chelator scaffold for the development of MMP inhibitors that was discovered by use of a metalloprotein-focused chelator fragment library.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Jacobsen
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fullagar
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Miller
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
mesh_terms: D000942:Antigens, Bacterial / Q000737:chemistry; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003300:Copper; D015195:Drug Design; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D007501:Iron; D008024:Ligands; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry*; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry; D015032:Zinc
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002614:Chelating Agents; D006912:Hydroxyquinolines; D008024:Ligands; D016859:Lipoxygenase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D013449:Sulfonamides; C030325:anthrax toxin; D003300:Copper; D007501:Iron; D052247:Nitric Oxide Synthase Type II; D014442:Monophenol Monooxygenase; D020782:Matrix Metalloproteinases; D015032:Zinc