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.
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DOS fragments grow hits in several directions at once
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Compound 1 was the first binder among about 1300 previous fragment soaks.
This initial screen resulted in the serendipitous discovery of 1 as a covalent binder of PBP3 (PDB: 6Y6Z, ), which strikingly was the first binder identified amongst approximately 1300 previous fragment soaks (see Table S1 for further details).
The DOS library was used at 500 mM in d6-DMSO.
The DOS library was screened in a racemic fashion to provide both enantiomers and was used in a 500 mM format in d 6 -DMSO.
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.
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