Dicovering interaction mode of specific carbaborane derivatives with GPCRs at Vanderbilt University

/ March 17, 2015/ News

by Peter Schmidt (postdoc at Leipzig University): GPCRs have been shown to play a crucial role in a variety of diseases, such as obesity, metabolic diseases and cancer. Accordingly, they are an attractive target for the investigation of new pharmaceuticals. Di-carba-closo-dodecaboranes(12) (closo-C2B12H12 or carbaboranes) were recently established as pharmacophores. Their unique properties (hydrophobicity, three-dimensional aromaticity, etc.) make them interesting targets for drug development.

In this project, specific carbaborane derivatives will be prepared and used either as conjugates with peptides of the melanotropin (MSH) or neuropeptide Y (NPY) family, or as small molecules that impart their action via GPCRs to study and understand their influence on the selectivity and activity. NPY binds to four so-called Y-receptors, MSH to five so called MC-receptors that all belong to the family of GPCRs. Especially MC4, Y2 and Y4 receptors are of significance as they play an important role in metabolic diseases. Efforts to develop single-subtype specific ligands often suffer from unwanted affinity to other receptors with similar binding mode. We have already shown that modification of NPY analogs with carbaboranes or carbaborane analogs of nonsteroidal anti-inflammatory drugs (NSAIDs) can influence the selectivity and activity.


Our designed specific carbaborane derivatives will be docked into the GPCR binding pockets using molecular modeling to reveal the biological relevant interaction mode. The docking solutions will than be varified by experimental data, aquired in distance EPR measurements. In the groups Daniel Huster and Peter Schmidt at the Leipzig University protocols have been established to express, purify and refold the GPCRs in a native-like lipid environment. Our collaborators at the Vanderbilt University have the equipment and the experience to perform molecular modeling and EPR on receptor proteins and their interaction partners.

Together with the collaborators at the Vanderbilt University, I adapt the preparation protocols for the EPR measurements and conduct experimental studies. These studies will provide distance restraints between specific residues in the derivatives and the GPCRs, which will decrease the number of docking solutions drastically and directly influences the design of the carbaborane derivatives for receptor specificity. Finally, we hope to ensure the fruitful long-term collaboration between the numerous groups, which is prerequisite for success of this project.