Drug Discovery from Protein-Protein Interactions by NMR
Sprache des Vortragstitels:
Englisch
Original Tagungtitel:
17. Österreichische Chemietage 2017
Sprache des Tagungstitel:
Deutsch
Original Kurzfassung:
In the past few years the search for active compounds that have a therapeutic influence
on protein-protein interactions has been intensified. The present work focuses on our
attempt to combine methods from molecular and structural biology with computational
approaches to identify small organic compounds that are potential protein-protein
interaction inhibitors.
The biological target used is the complex of crucial proteins in fatty acid biosynthesis,
Acp (acyl carrier protein) with AcpS (acyl carrier protein synthase), from
Staphylococcus aureus. Both proteins show a high homology, not only to other cocci, at
sequence and structural level. Therefore, we can expect that compounds which inhibit
the bacterial Acp-AcpS interaction should have antibiotic activity.
To analyze the Acp-AcpS interaction more thoroughly, both proteins were produced
recombinantly. Peptides containing parts of the proteins (Acp or AcpS) were
synthesized and interaction studies of these peptides with the whole proteins were
performed using biolayer-interferometry and NMR. Interacting residues between the
proteins were identified by titrations and TCS NMR (Transferred cross saturation)
experiments.
One of the final goals of the experiments described above is to use the available
structural information for deriving pharmacophore models, which in turn can then be
employed for virtual screening. We have derived pharmacophore models starting from
the available Acp-AcpS complex of Staphylococcus aureus (PDB: 4DXE), including
information about interacting residues from the NMR experiments.
Forschungs-