Repurposing Suzuki Coupling Reagents as a Directed Fragment Library Targeting Serine Hydrolases and Related Enzymes

Area of Science:

• Biochemistry and Medicinal Chemistry
• Enzyme Inhibition
• Drug Discovery

Background:

• Serine hydrolases are a significant class of enzymes.
• Boronic acids are known reversible inhibitors of serine hydrolases.
• Boronic acids are widely available due to their use in coupling chemistry.

Purpose of the Study:

• To repurpose a collection of boronic acid fragments as a targeted library for serine hydrolases.
• To identify potent inhibitors of serine hydrolases using this fragment library.
• To demonstrate the utility of this approach against autotaxin, a phospholipase linked to cardiovascular disease.

Main Methods:

• Assembled a library of approximately 650 chemically diverse boronic acid fragments.
• Screened the library against serine hydrolases and related enzymes.
• Evaluated inhibitor efficiency using Lipinski's Rule of Three (LE > 0.6).

Main Results:

• Identified highly efficient inhibitor 'hits' (LE > 0.6) from the boronic acid fragment library.
• Demonstrated successful application of the approach against autotaxin.
• Validated the strategy for discovering potent serine hydrolase inhibitors.

Conclusions:

• Repurposing commercially available boronic acid fragments is an efficient strategy for targeting serine hydrolases.
• This directed fragment-based approach yields potent inhibitors.
• The method is applicable to enzymes of therapeutic interest, such as autotaxin in cardiovascular disease.