Towards understanding structural and dynamical determinants of G protein inhibition - rational design of novel subtype specific G-protein inhibitors

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Selective inhibition of G proteins, thus suppressing G protein-mediated signaling is an extremely powerful, pharmacological approach. Consequently, efforts have been undertaken to develop nucleotide-state-selective inhibitors for both, inactive guanosine diphosphate (GDP)-bound heterotrimers and active guanosine triphosphate (GTP)-bound Galpha or Gbeta-gamma dimers. To date very few Galpha subunit inhibitors with activity in whole cells have been reported. Identification of structural and dynamical determinants of G protein inhibition by the small molecule BIM and the Gq-specific depsipeptide FR900359 and compounds derived thereof (P1-3) through NMR spectroscopy and molecular dynamic simulations is one central issue of this project. Therefore, conformation of isolated G proteins (P2) with and without bound inhibitors in solution as well as in the solid state will be studied under various conditions utilizing various NMR techniques. The knowledge gained from these investigations accompanied with biological and pharmacological activity data (P5, P6) and NMR-derived inhibitor dissociation constants (this project) will guide the computer-assisted design of novel, subtype specific G protein inhibitors, in order to permit suppression of G protein signaling of each individual G protein subtype. Docking and MD simulations will be utilized to develop and preselect possible hit structures, which will be synthesized in P1, P2, and P3, respectively.