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.