Chelator fragment libraries for targeting metalloproteinases

Abstract

A chelator fragment library based on a variety of metal binding groups was screened against a metalloproteinase. Lead hits were identified and an expanded library of select compounds was synthesized, resulting in numerous high-affinity hits against several metalloprotein targets. The findings clearly demonstrate that chelators can be used to generate libraries suitable for fragment-based lead design (FBLD) directed at important metalloproteins.

Figure 1

Representative compounds from chelator fragment library 1 (CFL-1). For the full list of compounds, see the Supporting Information (figure S1).

Figure 2

Lead hits identified against zinc(II)-dependent metalloenzymes from a expanded library (eCFL-1) of 3,4-HOPO and 3,4-HOPTO fragments. 3,4-HOPO fragments are noted in italics.