DOS fragments grow hits in several directions at once
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.
Source
Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion
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DOS fragments grow hits in several directions at once
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
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.
What they did
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.
What they found
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.
The limits
What it doesn't show
The paper does not report optimized cellular potency or a clinical candidate—only early crystallographic hits and synthetic tractability.
Key terms
- DOS
- Diversity-oriented synthesis aimed at skeletally diverse, 3-D small molecules.
- Fragment-based drug discovery
- Screening small, weak binders then growing/linking them into potent ligands.
- PBP3
- Penicillin-binding protein 3, a bacterial cell-wall transpeptidase.
- Exit vector
- A designed site on a fragment where chemistry can grow the molecule.
- Covalent binder
- A fragment that forms a bond to an active-site residue (here Ser294).
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PBP3 hit 1 is notable because it was:
Common questions
What protein gave the first covalent DOS hit?
PBP3, compound 1 (PDB 6Y6Z).
How was the library screened?
Racemic, 500 mM in d6-DMSO, by X-ray (XChem).
How many analogues per hit were typically made?
Up to 14 in short sequences.
Which aromatic substitution soaked for CFI?
Only the p-fluoro analogue 28 of nine.
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