2026-10-12T15:25:42Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33867874 2026-09-16T18:15:45Z category_1 category_4 category_19 category_21 category_24 category_873 portal_63 item_type_3 month_year_09_2026

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 Johanna M. Jansen (2396272) Wilian Cortopassi (24999058) Daniel Fuller (3429635) Peter Ertl (329055) Eric Fang (3909934) Rishi Raj Gupta (1989082) Weiping Jia (44939) Jan Jiricek (619074) Mark Knapp (1693639) Andreas Lingel (2360662) John Manchester (2303572) Stephanie Moquin (18145682) Robert Moreau (276840) Debjani Patra (13280455) Liliana Pedro (4909141) Keith Pfister (2160925) Olivier Rene (24999061) Patrick Rudewicz (1693648) Manuel Saldivia (345698) Ansgar Schuffenhauer (2114851) Colin Skepper (24999064) Vanja Stojkovic (24580940) Jenny Tang (13133347) Paolo Tosco (1934965) Tiffany Tsang (3909943) Sarah Williams (2968740) Kelly Yan (14560392) Charles Wartchow (1936987) Biophysics Biochemistry Pharmacology Biotechnology Evolutionary Biology Chemical Sciences not elsewhere classified provide meaningful diversity native mass spectrometry molecular glue project fully elaborated molecules 2 main protease chemical property ranges based chemical spaces defined chemical space cover chemical space case studies include tractable hits applied scope chemical space considering ligand efficiency enhancing compound libraries scope ring systems efficient hit validation scope screening set chemical space scope principles studies exemplify preferred set ligand efficiency obtaining hits efficient hits compound quality compound acquisition scope concept yield low sufficient functionality selected physical organizing principle micromolar potency list triaging identifying ligand higher concentrations finding campaigns estrogen receptor demonstrated value changed practices biochemical methods 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. 2026-09-16T00:00:00Z Dataset Dataset 10.1021/acs.jcim.6c01654.s001 https://figshare.com/articles/dataset/The_Scope_Concept_Defined_Chemical_Space_for_Identifying_Ligand-Efficient_Tractable_Hits_Applied_to_Drug_Discovery_Targets_Trypanosomal_CLK1_14_3_3_Estrogen_Receptor-_and_SARS-CoV_2_Mpro/33867874 CC BY-NC 4.0