Organic synthesis
DOS fragments grow hits in several directions at once
Open access · cc by · source: Europe PMC
A modular diversity-oriented fragment library gave crystallographic hits on several proteins and then short, cheap sequences to many analogues, including a first covalent PBP3 fragment.
Key findings
Compound 1 was the first binder after ~1300 prior fragment soaks on PBP3, covalently linking Ser294. Up to 14 analogues per hit were accessible; only p-fluoro analogue 28 of nine aromatics soaked into CFI crystals; 1,4-isoxazole 29 bound but 1,5-isomer 30 did not.
Methodology
Authors screened a racemic DOS fragment set (500 mM in d6-DMSO) by X-ray crystallography, then used designed exit vectors—amide couplings, click chemistry, Cu(I) lactonizations—to elaborate hits such as the PBP3 covalent binder 1.
Limitations
The paper does not report optimized cellular potency or a clinical candidate—only early crystallographic hits and synthetic tractability.
How this study connects
Role on claims
Each row is a claim on a concept or method page where this paper supports, challenges, or qualifies the statement. Roles are hand-checked — not a model guess.
Not yet placed on a claim. This paper has study layers, but no concept page yet cites it as support, challenge, or qualifier.
Related papers in this topic
Same topic cluster — not a recommendation engine.