title: Multidimensional de novo design reveals 5-HT2B receptor-selective ligands.
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.
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 4, 8093 Zurich (Switzerland).
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Nadine
authors.initials: N
authors.lastname: Hauser
authors.forename: Daniel
authors.initials: D
authors.lastname: Reker
authors.forename: Michael
authors.initials: M
authors.lastname: Reutlinger
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wunderlin
authors.forename: Jacques
authors.initials: J
authors.lastname: Hamon
authors.forename: Guido
authors.initials: G
authors.lastname: Koch
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008024:Ligands; D044085:Microfluidics; D011485:Protein Binding; D044403:Receptor, Serotonin, 5-HT2B / Q000737:chemistry* / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism
chemical_list: D000588:Amines; D008024:Ligands; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists
keywords: GPCR; computer-assisted molecular design; drug discovery; microfluidics; organic synthesis