Light-Induced Unlocking Reactivity of Fragments for Fast Target-Guided Synthesis of Carbonic Anhydrase Inhibitors

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Kinetic Target-Guided Synthesis (KTGS) is a fragment-based drug discovery (FBDD) method where protein targets guide ligand assembly.
• In situ click chemistry is a common KTGS strategy but requires long incubation times and stable proteins.
• Limitations of traditional KTGS include prolonged reaction times and potential for false negatives.

Purpose of the Study:

• To integrate photochemistry with KTGS to accelerate inhibitor discovery.
• To overcome the limitations of traditional in situ click chemistry in KTGS.
• To expand the scope of KTGS to a wider range of biological targets.

Main Methods:

• Developed a novel photo-KTGS strategy by combining photochemistry with KTGS principles.
• Utilized light-induced reactions to facilitate fragment ligation.
• Applied the method for rapid identification of enzyme inhibitors.

Main Results:

• Successfully demonstrated the combination of photochemistry and KTGS for rapid enzyme inhibitor identification.
• Accelerated the fragment ligation reaction to a time scale of minutes.
• Expanded the reactivity window of traditional KTGS reactions.

Conclusions:

• Photochemistry integration significantly accelerates KTGS.
• Photo-KTGS broadens the applicability of fragment-based drug discovery.
• This approach enables faster and more efficient discovery of novel enzyme inhibitors.