Multidimensional De Novo Design Reveals 5‐HT2B Receptor‐Selective Ligands |
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| Authors: | Dr Tiago Rodrigues Nadine Hauser Daniel Reker Dr Michael Reutlinger Tiffany Wunderlin Dr Jacques Hamon Dr Guido Koch Prof Dr Gisbert Schneider |
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| Institution: | 1. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir‐Prelog‐Weg 4, 8093 Zurich (Switzerland);2. Novartis Institutes for BioMedical Research (NIBR), Novartis AG, 4056 Basel (Switzerland) |
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| 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. |
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| Keywords: | computer‐assisted molecular design drug discovery GPCR microfluidics organic synthesis |
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