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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antigens, Bacterial / chemistry
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Bacterial Toxins / antagonists & inhibitors
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Bacterial Toxins / chemistry
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Chelating Agents / chemical synthesis*
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Chelating Agents / chemistry
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Copper
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Drug Design
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Humans
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Hydroxyquinolines / chemical synthesis*
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Hydroxyquinolines / chemistry
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Iron
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Ligands
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Lipoxygenase Inhibitors / chemical synthesis
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Lipoxygenase Inhibitors / chemistry
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Matrix Metalloproteinase Inhibitors*
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Matrix Metalloproteinases / chemistry*
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Monophenol Monooxygenase / antagonists & inhibitors
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Monophenol Monooxygenase / chemistry
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / chemistry
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / chemistry
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Small Molecule Libraries
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Zinc
Substances
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Antigens, Bacterial
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Bacterial Toxins
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Chelating Agents
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Hydroxyquinolines
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Ligands
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Lipoxygenase Inhibitors
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Matrix Metalloproteinase Inhibitors
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Recombinant Proteins
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Small Molecule Libraries
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Sulfonamides
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anthrax toxin
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Copper
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Iron
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Nitric Oxide Synthase Type II
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Monophenol Monooxygenase
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Matrix Metalloproteinases
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Zinc