Practical_Fragments

A blog founded by Teddy Zartler and run by Dan Erlanson for Fragment-based Drug Discovery devotees to discuss non-confidential issues regarding fragments.

[Practical_Fragments @PracticalFrag]

Sometimes a classic warhead is not actually a warhead. Serendipity with hub protein 14-3-3:
https://t.co/CA0IT4zJuc
@ACSBioMed @RichardDoveston
@Leicesterchem @ACSMedChemLett

[Practical_Fragments @PracticalFrag]

From fragment to clinic: the story of VVD-214, covalent allosteric inhibitor of WRN helicase, and part 3 of 3 for our round-up of fragments against this flexible, fascinating cancer target
https://t.co/On3SWYlWD6
@bmsnews @VividionRx @ACSPublications

[Practical_Fragments @PracticalFrag]

Crystallographic fragment screen finds cryptic pockets on oncology target WRN, protein co-folding software suggests binding modes to generate covalent inhibitors
https://t.co/pOQ6aQLOoN

[Practical_Fragments @PracticalFrag]

Finding fragments when a protein has many conformations: Merck team finds and advances fragments against synthetic lethal cancer target WRN helicase
https://t.co/JzOcJihsFC

[Practical_Fragments @PracticalFrag]

Watch out for X-ray structures that assume every protein has a ligand. A new analysis suggests one-third should show partial binding. Just one-tenth in the PDB actually do:
https://t.co/ZUk42fsZYF
@Structure_CP @StJude

[Practical_Fragments @PracticalFrag]

Latching into and breaking out of a cryptic pocket:
Efforts toward a chemical probe of anti-virulence bacterial target DsbA
https://t.co/S6oZ6LJxp2
@ACSPublications  @MIPS_Australia

[Practical_Fragments @PracticalFrag]

A wrap-up of fragment-relevant talk at San Diego's sunny @CHI_Healthtech
https://t.co/zGXBnLufPr
GPCRs, NMR, hit optimization, platform development, covalent drugs, direct-to-biology, computational screening, molecular glues, and more

[Practical_Fragments @PracticalFrag]

Targeted protein degradation in cancer cells? Fragment screen plus optimization yields cell-active ligand on the E3 end for a selective PROTAC:
https://t.co/QPVV1iEMZ7
@AmerChemSociety @JMedChem

[Practical_Fragments @PracticalFrag]

SARS-CoV-2s papain-like protease is a tough target.
Researchers @VanderbiltChem advance fragment hit non-covalently and covalently:
https://t.co/Rs137A4VUO
@ACSMedChemLett @JMedChem @AmerChemSociety

[Practical_Fragments @PracticalFrag]

The laxest ligand efficiency metric, at last!
https://t.co/jR9C78Pbo7

[Practical_Fragments @PracticalFrag]

A practical metric from @VividionRxto to help weed out nonspecific, generally-reactive covalent ligands:
Ligand reactivity efficiency (LRE)
https://t.co/p5VcVV2ace
@ACSPublications

[Practical_Fragments @PracticalFrag]

Artifacts against a SARS-CoV-2 target exposed!
A cautionary tale shows the importance of compound resynthesis and purification
https://t.co/GSGEEXlkBn
@ACSPublications

[Practical_Fragments @PracticalFrag]

Before trusting a chemical probe or advancing a lead compound, a selectivity check is crucial. But cell-free (DiscoverX @EurofinsGroup ) and cell assays (NanoBRET @promega) can yield different answers for kinases.
https://t.co/aHxwxoy56o
@Chemical_probes @ACSPublications

[Practical_Fragments @PracticalFrag]

A technique to find the binding mode of fragment-sized millimolar binders? Hydrogen/deuterium exchange MS (HDX-MS) gets at least 2/3 for CyclophilinD:
https://t.co/bIlerSAom0

[Practical_Fragments @PracticalFrag]

Dimer detection, binding kinetics, and more: A wealth of biophysics techniques from @novalix_pharma conference in San Diego:
https://t.co/fwVGL9YWci

[Practical_Fragments @PracticalFrag]

3D fragment hit rates are lower, but perhaps advancement goes faster. A shapely scaffold yields an impressive hit for the histamine H1 receptor.
https://t.co/IAsA4Tl9D7
@RoySocChem

[Practical_Fragments @PracticalFrag]

A fragment becomes a trimer and a potent inhibitor of lipoprotein(a) formation. How a rule-of-3 compliant fragment became an unconventional but promising phase 3 candidate for CV disease:
https://t.co/TQU2zgTqXU
@ProfSNicholls ⁩ ⁦@MonashVHI⁩⁦ @Nature⁩ @EliLillyandCo

[Practical_Fragments @PracticalFrag]

Crystallographic SAR
Hits from high-throughput X-ray screens of crude mixtures can be broken down into fingerprints that identify new binders that crude extract X-ray screening miss
https://t.co/BLGYrOwxs5
@UniofOxford @DiamondLightSou @FrankvonDelft

[Practical_Fragments @PracticalFrag]

Fragment merging finds submicromolar binders for a kink in a leucine zipper
https://t.co/AmQrcBvm4h
In @NatureComms, @Novartis researchers find binders for a difficult melanoma target, the transcription factor MITF

[Practical_Fragments @PracticalFrag]

The shapeliness debate has run for decades. A new analysis compares metrics of molecular 3D shape
https://t.co/gWJm5uTZYK