Flashcard library · Chemistry · PaperFren
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.
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What practical problem in fragment optimisation did the DOS library target?
Need for 3-D fragments with multidirectional, synthetically tractable exit vectors.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
How was the DOS library formatted for crystallographic screening?
Racemic, 500 mM in d6-DMSO.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
What was special about PBP3 hit 1?
It was a covalent binder and the first hit after ~1300 previous fragment soaks (PDB 6Y6Z).
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
Which serine did analogues of 1 covalently modify?
Ser294, with H-bonds to Asn351, Ser349 and Thr487.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
How many analogues could be made per hit, despite quaternary centres?
Up to 14 in short sequences from cheap commercial materials.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
Which of nine substituted aromatics (20–28) soaked into the CFI crystals?
Only the p-fluorine analogue 28 (PDB 5R4T).
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
Did both isoxazole regioisomers bind?
No—1,4-isomer bound; 1,5-isomer 30 did not.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
How were unsaturated lactone scaffolds 2–7, 10 and 11 closed?
Cu(I)Br cyclisation of the final precursors.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
What did the phenol of analogue 6 appear to do in the pocket?
Project into a hydrophobic cleft and π–π stack with Tyr407 and Tyr409 (PDB 6Y6U).
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
Which proteins besides PBP3 gave hits?
CFI 25 and activin A, four hits in total across functionally diverse proteins.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified
Where is the library available for others to screen?
Via the XChem platform.
Source: Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion · DOI · quote verified