Masking thiol reactivity with thioamide, thiourea, and thiocarbamate-based MBPs

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Drug Discovery

Background:

• Metalloenzymes play crucial roles in biological processes, and their dysregulation is implicated in various diseases.
• Fragment-based drug discovery (FBDD) is an effective strategy for developing novel therapeutics.
• Developing stable and effective metal-binding pharmacophores (MBPs) is essential for targeting metalloenzymes.

Purpose of the Study:

• To introduce stable, sulfur-based molecules as novel metal-binding pharmacophores (MBPs).
• To evaluate the potential of these MBPs in metalloenzyme fragment-based drug discovery (mFBDD).
• To investigate the binding capabilities of these MBPs with specific Zn(II)-dependent metalloenzymes.

Main Methods:

• Synthesis and characterization of thioamides, thioureas, and thiocarbamates as MBPs.
• Assessment of MBP reactivity and bioactivity through in vitro assays.
• Structural studies to elucidate binding modes with target metalloenzymes.

Main Results:

• Thioamides, thioureas, and thiocarbamates were confirmed as stable, sulfur-based MBPs.
• These MBPs demonstrated significant ligand capabilities for Zn(II)-dependent metalloenzymes.
• Binding was successfully demonstrated for human carbonic anhydrase II (hCAII) and matrix metalloproteinase-2 (MMP-2).

Conclusions:

• Sulfur-based thioamides, thioureas, and thiocarbamates represent a promising class of MBPs.
• These MBPs are suitable for application in metalloenzyme fragment-based drug discovery (mFBDD).
• The findings support the development of new therapeutics targeting metalloenzymes like hCAII and MMP-2.