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

The advent of ultra-large libraries of drug-like compounds has significantly broadened the possibilities in structure-based virtual screening, accelerating the discovery and optimization of high-quality lead chemotypes for diverse clinical targets. Compared to traditional high-throughput screening, which is constrained to libraries of approximately one million compounds, the ultra-large virtual screening approach offers substantial advantages in both cost and time efficiency. By expanding the chemical space with compounds synthesized from easily accessible and reproducible reactions and utilizing a large, diverse set of building blocks, we can enhance both the diversity and quality of the discovered lead chemotypes. In this study, we explore new chemical spaces using reactions of sulfur(VI) fluorides to create a combinatorial library consisting of several hundred million compounds. We screened this virtual library for cannabinoid type II receptor (CB