Identifying Chelators for Metalloprotein Inhibitors Using a Fragment-Based Approach

• Published in: Journal of medicinal chemistry 2011-01, Vol.54 (2), p.591-602
• Main Authors: Jacobsen, Jennifer A, Fullagar, Jessica L, Miller, Melissa T, Cohen, Seth M
• Format: Article
• Language: English
• Subjects: Antigens, Bacterial - chemistry; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - chemistry; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Copper; Drug Design; Humans; Hydroxyquinolines - chemical synthesis; Hydroxyquinolines - chemistry; Iron; Ligands; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases - chemistry; Monophenol Monooxygenase - antagonists & inhibitors; Monophenol Monooxygenase - chemistry; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - chemistry; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - chemistry; Small Molecule Libraries; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Zinc
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101266s

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 IC50 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.