Multidimensional de novo design reveals 5-HT2B receptor-selective ligands.
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.
Rodrigues, T; Hauser, N; Reker, D; Reutlinger, M; Wunderlin, T; Hamon, J; Koch, G; Schneider, G
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