Presented at the Global Medicinal Chemistry and GPCR Summit. To find out more, visit:
www.global-engage.com
Andreas Brunschweiger, an Independent Group Leader at TU Dortmund, discusses the limitations of DNA-encoded compound libraries (DELs) and getting around these.
3. Identification of bioactive molecules
for chemical biology and medicinal chemistry?
CHEMISTRY BIOLOGY
HYPOTHESIS
?
Peptides
Macrocycles
Oligonucleotides
Small Molecules
PROBE
Natural products
CombiChem
Signaling cascade
Protein-Protein Interaction
Splicing
Cell fate
Differentiation
Autophagy
The gap between chemistry and biology
10. The chemical space of DELs: appendage diversity
5 x 108 compounds
(Harris, J Med Chem.2016)
1 x 105 compounds
(Franzini, Angew Chem Int Ed. 2015)
3 x 106 compounds
(Young, ACS Med Chem Lett. 2015)
4 x 108 compounds
(Kollmann, Bioorg Med Chem.2014)
DNA-compatible, robust, high-yielding reactions with broad scope
large numbers, high appendage diversity
few heterocycle-forming reactions
few reactions confering three-dimensionality:
low structural diversity
Salamon, ACS Chem. Biol. 2016
Klika Skopic, Med. Chem. Commun.2016
16. DEL screen: results
POI: Streptavidin
The 2nd ranking streptavidin binder
Identified in a second DEL
17. • adapting the scaffold to the needs of DNA
• only appendage diversity
• methodology restricted: two reactions
Coverage of chemical space? Perspective??
encoded library
synthesis
25. TIDEC
Klika Skopic, Chem. Sci. Chem. Sci., 2017, 8, 3356-3361
Brunschweiger, Krause, Antonchick, et al. PCT/EP2016/081845
HexT
Initiating library synthesis with the hexT
26. hexT: recognition by T4 ligase
fluorescence scan
detection of
DNA
stain 5,5% agarose gel; 75 min; 150V;
gel stain: Midori Green
grey: primer sequence
34. aq. NH3
HPLC of the crude hexT-conjugate
Ms (calc.): 2391.8
Ms (found):2392.3
aq. NH3
Access to hexT-pyrazoline conjugates.
35. Towards pyrazol(in)e libraries
71 amino-substituted hexT-pyrazol(in)es synthesized
selection of reaction conditions: access to two core structures
scope: aromatic and branched aliphatic aldehydes, diverse hydrazides,
aliphatic, and aromatic alkynes
38. Bode J. W.et. al. Org. Lett., 2014, 16,1236-1239.
mass calc.= 2260.6
mass found= 2261.6
SnAP reagent
MALDI-MS of the purified
hexT-small molecule conjugate
Expanding chemistry: Cu(II)-mediated cyclization
HPLC trace
of the crude
39. Expanding chemistry: Ugi reaction
mass calc.= 2256.7
mass found= 2257.5
MALDI-MS of the purified
hexT-small molecule conjugate
HPLC trace
of the crude
45. The DNA-Team
Mateja Klika Skopic
Hazem Salamon
Kathrin Jung
Olivia Bugain
Chemistry
Prof. Ralf Weberskirch, TU Dortmund
Dr. Andrea Ernst
Hanne Petersen
Prof. Norbert Krause, TU Dortmund
Dr. Bernd Wagner
Justin Schieven
Financial support from
is most gratefully acknowledged!
Cheminformatics
Dr. Tuomo Kalliokoski, LDC Dortmund
Dr. Oliver Koch, TU Dortmund
Faculty
Prof. Daniel Rauh
Prof. Herbert Waldmann
Analysis of sequencing
data
Dr. Michael Blank
Dr. Carsten Gröber
Screening
Prof. Günter Mayer, Universität Bonn
Franziska Pfeiffer, Universität Bonn
46. Presented at the Global Medicinal
Chemistry and GPCR Summit
To find out more, visit:
www.global-engage.com