Abstract
<jats:p>The 5-HT receptor 2A (5-HT2AR) is a G protein-coupled receptor (GPCR) activated by serotonin and one of the main targets for the development of antipsychotic drugs, e.g. against schizophrenia. There is evidence that the activation of certain transducers downstream of the receptor over others may lead to fewer side effects. For the development of new drugs with a more favorable side-effect profile than existing medications, therefore, a deep understanding of the correlations between the chemical structure of 5-HT2AR ligands and the panel of transducers that are activated after ligand binding is necessary. In this work, we have computationally screened large databases for previously undescribed ligands of the 5-HT2AR and pharmacologically assessed four transducers–activation of Gq, G15, Gz and recruitment of β-arrestin–with BRET assays. Each molecule was tested in agonist-and antagonist mode, resulting in diverse transducer engagement profiles for 37 ligands of different chemotypes. Receptor:ligand interactions were investigated through Molecular Dynamics simulations and Protein-Ligand Interaction Fingerprints. Our data highlight how the vastness and density of chemical space enable incredibly diverse texture in the signaling outcome, namely that even molecules similar to serotonin itself show vastly divergent signaling outcomes, occasionally even with pathway bias. This opens doors for exploring new pharmacology.</jats:p>