Identifying chelators for metalloprotein inhibitors using a fragment-based approach.

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biochemistry

Background:

• Fragment-based lead design (FBLD) is a powerful strategy for discovering novel inhibitors.
• Metalloenzymes play critical roles in various biological processes and are important drug targets.

Purpose of the Study:

• To identify new metal-binding groups for metalloenzyme inhibitors using a chelator fragment library.
• To explore the potential of 8-hydroxyquinoline as a scaffold for developing matrix metalloprotease (MMP) inhibitors.

Main Methods:

• Screening of a 96-compound chelator fragment library (CFL-1.1) against five MMPs, anthrax lethal factor (LF), 5-lipoxygenase (5-LO), and tyrosinase (TY).
• Structure-based design and synthesis of elaborated fragments based on initial hits.
• Enzyme inhibition assays to determine IC50 values.

Main Results:

• High hit rates (29-60%) were observed for CFL-1.1 against the tested metalloenzymes.
• Fragment hits exhibited excellent ligand efficiencies (0.4-0.8 kcal/mol).
• Elaborated 8-hydroxyquinoline fragments demonstrated potent inhibition against MMP-2 (low micromolar IC50 values).

Conclusions:

• The chelator fragment library effectively identified diverse metal-binding groups for various metalloenzymes.
• 8-Hydroxyquinoline is a promising scaffold for developing novel MMP inhibitors.
• FBLD with focused fragment libraries accelerates the discovery of potent metalloenzyme inhibitors.