Multidimensional De Novo Design Reveals 5‐HT2B Receptor‐Selective Ligands
Tiago Rodrigues, Nadine Hauser, Daniel Reker, Michael Reutlinger, Tiffany Wunderlin, Jacques Hamon, Guido Koch, Gisbert Schneider · Angewandte Chemie · 2014
Abstract We report a multi‐objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer‐generated 5‐HT2B receptor ligands with accurately predicted target‐binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand‐efficient 5‐HT2B modulators with sustained cell‐based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics‐assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.