For diseases such as cancer, the Gα subunits of heterotrimeric G proteins are attractive drug targets as alternatives to G protein-coupled receptors (GPCRs). Britta and Ajay contributed to the development of new modulators for the Gαi/s subfamilies providing insights into G protein-mediated signal transduction. In this work, two peptides were obtained that showed guanine-nucleotide exchange modulator (GEM)-like activity towards Gαi and Gαs in cell-based assays. This was complemented by an array of computational analyses ranging from homology modeling, detection of binding sites, molecular docking and molecular dynamics simulations.
This BioSolveIT webinar will cover ground on a wide spectrum of disciplines ranging from biochemistry, medicinal chemistry, to biomolecular modeling and simulations. First, Britta will show the selection of a promising peptide hit from a high-throughput screening approach and its further optimization with respect to drug-like properties, including the results from the activity assays of the lead structure and the optimized peptides. Ajay will then provide a plausible, molecular basis for the observed effects based on the computational investigations done. In summary, these results provide new insights into the G protein-mediated signal transduction and a further step towards specific targeting of the Gαi/s subunit by peptidic modulators.