testing the robustness of pharmacophore models using molecular dynamics simulations

Marcus Wieder, University of Vienna, Department of Pharmaceutical Chemistry

Nearly 90% of the protein structures in the PDB are determined by X-ray crystallography. Protein structures in a crystalline state are liable to be affected by the crystal environment. Moreover, the obtained electron density represents the ensemble average of the different conformations present in the crystal. This leads to two problems: on the one hand the average of two conformations is not necessarily the state that is most visited and on the other hand the average structure might even be a conformation that is very strained. As a result up to 30 % of the ligand structures in the PDB database are questionable. Also the static view on the protein-ligand structure hides all dynamic events. But molecular systems are inherently dynamic and display a wide range of motion.

In our work we try to evaluate the impact crystallized ensemble average has on the generation of structure-based pharmacophore models obtained with LigandScout. We use molecular dynamic simulations utilizing the CHARMM software to study the dynamic of the system and analyze the interactions of the protein-ligand system as a function of time without non-physiological contacts that are present in the crystal. In this talk I will present the results of this analysis.


Short CV

Marcus Wieder started his PhD work on pharmacophore models in summer 2014 in the Department of Pharmaceutical Chemistry at the University of Vienna under the supervision of Univ. Prof. Mag. Dr. Thierry Langer and Univ.Prof Mag. Dr. Stefan Boresch.

Before he came to Vienna in 2008, Marcus studied Genetics in Salzburg and obtained his Master's Degree in Molecular Biology in 2013 and his Master's Degree in Chemistry in 2014.