The Scope Concept: Defined Chemical Space for Identifying Ligand-Efficient, Tractable Hits Applied to Drug Discovery Targets Trypanosomal CLK1, 14–3–3/Estrogen Receptor-α, and SARS-CoV-2 Mpro

Abstract

Scope is a hit-finding concept that explores a chemical space in between fragments and fully elaborated molecules from traditional low molecular weight (LMW) libraries. It emphasizes high medicinal chemistry tractability through a focus on compound quality, ligand efficiency, and selected physical-chemical property ranges. The Scope chemical space definition seeks to strike a balance between the ability to cover chemical space with a 10k–50k compound set for medium-throughput screening and obtaining hits with sufficient functionality to yield low- to mid-micromolar potency. Scope chemical space is distinct from other rule-based chemical spaces, and we introduce the concept of Scope ring systems (ring-X-ring) as both a foundation for intentional functionalization targeting sufficient potency and as an organizing principle for characterizing and enhancing compound libraries. A Scope screening set has been designed from the Scope chemical space for hit finding with SPR, native mass spectrometry, DSF, and biochemical methods. This Scope set maintains comparable primary hit rates to general diversity sets even when screening at higher concentrations, which allows for efficient hit validation. The Scope set outperforms diversity sets when considering ligand efficiency and hit rates after counter-screening, which makes it a preferred set. Case studies include the trypanosomal CLK1 kinase target, a molecular glue project with 14–3–3 and estrogen receptor-α, and the SARS-CoV-2 main protease. These studies exemplify how the 10k Scope set delivers diverse and ligand-efficient hits with tractable potency across diverse binding sites and support the idea that a carefully designed 10k Scope set can provide meaningful diversity for screening in a broad drug discovery portfolio. The Scope principles have demonstrated value in hit-finding campaigns and have changed practices for compound acquisition, hit-list triaging, and screening.