Philipps-University of Marburg (PUM)

Philipps-University of Marburg has been a place of research and teaching for nearly five centuries. Its pharmacy department is the largest in the country and the first Medicinal Chemistry worldwide was opened 1609 in Marburg. There are nearly 26.500 students and 4,000 employees. Short course durations, outstanding research, qualified training for the next generation and intensive international networking distinguish Philipps-University.

Marburg group in the AEGIS consortium: In order to find new lead structures for the development of a drug, our group is heavily engaged in establishing strategies for fragment-based lead discovery(FBLD), a crystallographic approach starting with small probes (≤ 200 Da, so called ‘fragments’) as initial entry points. Based on the crystal structure of such hits, more potent leads are developed by growing the initial fragment into the binding pocket. Since in all of these projects the influence and binding of water molecules takes an essential impact, the group embarked onto a detailed study of water molecules and their role in ligand binding. These investigations require crystallographic studies at extremely high resolution with X-rays and with neutrons as well. Furthermore, molecular dynamics simulations help to understand the influence of water on binding. An additional focus of the group is put on the understanding of protein-protein interfaces and how they are stabilized energetically and kinetically. Strategies are developed to perturb and destabilize such interfaces by tailored mutations and by interference via small molecule binding. Apparently, also in this case water penetration takes decisive influence on the protein- protein interface formation and stability.

H. Köster, T. Craan, S. Brass, C. Herhaus, M. Zentgraf,  L. Neumann, A. Heine, G. Klebe. A Small Nonrule of 3 Compatible Fragment Library Provides High Hit Rate of Endothiapepsin Crystal Structures with Various Fragment Chemotypes J Med Chem, 54 (22) (2011) 7784-96, http://dx.doi.org/10.1021/jm200642w

Biela, N.N. Nasief, M. Betz, A. Heine, D. Hangauer, G. Klebe. Dissecting the hydrophobic effect on molecular level: the role of water, enthalpy, and entropy in ligand binding to thermolysin Angew. Chem. Int. Ed., 52 (6) (2013) 1822-28, http://dx.doi.org/10.1002/anie.201208561 

E. Rühmann, M. Betz, A. Heine, G. Klebe.Fragment Binding Can Be Either More Enthalpy-Driven or Entropy-Driven: Crystal Structures and Residual Hydration Patterns Suggest Why. J. Med. Chem., 2015, 58 (17), 6960–71, http://dx.doi.org/10.1021/acs.jmedchem.5b00812

S. Jakobi, T.X. Nguyen, F. Debaene, A. Metz, S. Sanglier-Cianférani, K. Reuter, G. Klebe. Hot-spot analysis to dissect the functional protein-protein interface of a tRNA-modifying enzyme. Proteins 82 (10), (2014), 2713-32, http://dx.doi.org/10.1002/prot.24637