For almost a quarter of a century, the Klebe research group was worked in research and teaching at the Institute of Pharmaceutical Chemistry of the Philipps University in Marburg. During these years, the group consisted of 30 - 45 employees as master students, diploma students, doctoral students and postdocs. Our research focus covered a wide range of aspects of structure-based drug design.
The cause for the development of many diseases is very often the malfunction of certain proteins in cells of the human body. In order to treat such diseases or symptoms triggered by these malfunctions, drug therapy attempts to modulate the activity of the malfunctioning proteins which could be involved in signal transduction, metabolic pathways, enzymatic transformations or protein activation, for example.
The active ingredient suitable for a therapy is intended to change the function of a protein by binding to this protein. Therefore, the special interest of our group was to investigate how small molecules interact with their target proteins in a disease situation and to change thereby their properties and functions. The basic prerequisite for all these processes is the specific and selective recognition of the interacting biomolecules.
To approach these questions, we have developed both, experimental and computer-based methods and applied them to problems of practical relevance. On the one hand, our research group covered the entire process of protein structure determination; from crystallization via X-ray and neutron diffraction to structure determination and refinement in combination with activity measurements, in which the binding kinetic and thermodynamic properties of the protein-ligand complexes are determined. Our group has contributed with more than 1500 structures to the huge repository of the protein database PDB. Recently, we have focused our developments on fragment-based lead discovery using the increasingly accelerated protein crystallography. For example, at the synchrotron Bessy II, HZB in Berlin, we could established with our colleagues in Berlin a fragment beamline mainly for academic users. From within the group, the biotech company CrystalsFirst was founded, which focuses on the development of methods for crystallographic fragment screening and structure-based fragment optimization. Furthermore, many in silico methods have been developed and applied in the group, which correlate information about protein binding sites and receptor-ligand complexes, generate and evaluate energetically docking solutions, compare and predict structural data of proteins and ligands, and study the solvate structure around ligands and proteins. Internationally applied computer tools such as CoMSIA, AFMoC, DrugScore, Relibase or Cavbase have been developed and improved within the group. If you are interested in a more detailed description of our research, please click here.
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