Deciphering Specificity Determinants for FR900359‐Derived Gqα Inhibitors Based on Computational and Structure–Activity Studies

Direct targeting of intracellular Gα subunits of G protein‐coupled receptors by chemical tools is a challenging task in current pharmacological studies and in the development of novel therapeutic approaches. In this study we analyzed novel FR900359‐based analogs from natural sources, synthetic cyclic peptides, as well as all so‐far known G_qα inhibitors in a comprehensive study to devise a strategy for the elucidation of characteristics that determine interactions with and inhibition of G_q in the specific FR/YM‐binding pocket. Using 2D NMR spectroscopy and molecular docking we identified unique features in the macrocyclic structures responsible for binding to the target protein correlating with inhibitory activity. While all novel compounds were devoid of effects on G_i and G_s proteins, no inhibitor surpassed the biological activity of FR. This raises the question of whether depsipeptides such as FR already represent valuable chemical tools for specific inhibition of G_q and, at the same time, are suitable natural lead structures for the development of novel compounds to target Gα subunits other than G_q.