Virtual Screening of a Chemically Diverse "Superscaffold" Library Enables Ligand Discovery for a Key GPCR Target

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Drug Discovery

Background:

• Ultra-large virtual screening accelerates the discovery of drug candidates.
• Traditional high-throughput screening is limited by library size and cost-efficiency.
• Expanding chemical space with diverse building blocks enhances lead chemotype quality.

Purpose of the Study:

• To explore new chemical spaces using sulfur(VI) fluoride reactions for ultra-large library generation.
• To virtually screen this library for cannabinoid type II receptor (CB2) antagonists.
• To validate the effectiveness of this approach in identifying novel lead compounds.

Main Methods:

• Generated a combinatorial library of several hundred million compounds via sulfur fluoride exchange reactions.
• Performed structure-based virtual screening targeting the cannabinoid type II receptor (CB2).
• Synthesized and tested top-predicted compounds for in vitro CB2 binding and functional antagonism.

Main Results:

• Achieved an experimentally validated hit rate of 55% for CB2 antagonists.
• Demonstrated the successful diversification of ultra-large chemical spaces.
• Identified high-quality lead compounds for a significant clinical target.

Conclusions:

• Sulfur fluoride exchange reactions are effective for diversifying ultra-large chemical libraries.
• Ultra-large virtual screening is a cost- and time-efficient method for drug discovery.
• This strategy facilitates the identification of novel lead compounds for important biological targets like CB2.