QuantumBio will be co-sponsoring the Perspectives in Applied Computational Methods session at the 2012 American Chemical Society meeting in San Diego, CA March 26-27. The following two abstracts will be presented:
156 – Probing secondary Glutaminyl-Cyclase (QC)-inhibitor interactions applying an in silico-analysis/site-directed mutagenesis approach
Mirko Buchholz1, mirko.buchholz@probiodrug.de, Birgit Koch2, Michael Wermann2, Ulrich Heiser1, Stephan Schilling2, Hans-Ulrich Demuth1,2. (1) Department of Chemistry, Probiodrug AG, Halle, Germany, (2) Department of Enzymology, Probiodrug AG, Halle, Germany
Glutaminyl Cyclases have been identified as catalysts of pyroglutamyl formation at the N-terminus of Ab-peptides deposited in Alzheimers Disease. The modification enforces amyloidogenicity, likely contributing to progression of the disorder. Inhibitors of QC attenuated AD-like pathology in animal models of AD. We characterized the binding mode of the inhibitor PBD150 applying a combined approach of in-silico analysis and site directed mutagenesis. PBD150 co-crystallized with QCs reveals different poses of a derivatized phenyl ring. These poses were characterized via a semi-empirical approach based on the linear-scaling divide-and-conquer methodology, and further analyzed using the SE-COMBINE approach. Following this approach, site directed mutagenesis was performed to replace key amino acids of the active site. In contrast to metal binding groups, the Ki-values of PDB150 are affected drastically for some variants, suggesting a specific probing of secondary interactions between PBD150 and QC.
Monday, March 26, 2012 02:05 PM
Perspectives in Applied Computational Methods (02:00 PM – 03:55 PM)
Location: San Diego Convention Center
Room: Room 28D
251 – Protein co-crystal structures: We can do a lot better
Charlles H. Reynolds, chuck_reynolds@me.com, Lance M. Westerhoff, Oleg Borbulevych. QuantumBio, State College, Pennsylvania 16801, United States
The advent of protein crystallography some 30 years ago opened a new chapter in drug discovery. With recent advances in structural biology the number of protein structures that are available to drive drug design has exploded. It is becoming increasingly clear, however, that the quality of these structures has, in many cases, much room for improvement. Typical structure refinement software includes fairly drastic approximations and may not be at all well suited to the complex drug molecules found in co-crystal structures. We have developed a QM-based refinement algorithm that provides for a significant improvement in x-ray structure refinement, particularly in the critical ligand-binding site. We have also developed a complementary pairwise-decomposition scheme that allows us to move beyond a simple picture to include a detailed and quantitative protein-ligand interaction map. We will discuss how this new paradigm can fundamentally alter the quality of protein crystal structures, and provide improved starting points for drug discovery.
Tuesday, March 27, 2012 02:05 PM
Perspectives in Applied Computational Methods (02:00 PM – 03:55 PM)
Location: San Diego Convention Center
Room: Room 28D