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Multidimensional De Novo Design Reveals 5-HT2BReceptor-SelectiveLigands

Rodrigues, Tiago, Hauser, Nadine, Reker, Daniel, Reutlinger, Michael, Wunderlin, Tiffany, Koch, Guido, Hamon, Jacques and Schneider, Gisbert (2015) Multidimensional De Novo Design Reveals 5-HT2BReceptor-SelectiveLigands. Angewandte Chemie. International edition, 54 (?). pp. 1553-1555. ISSN 1521-3773; 0570-0833; 1433-7851


We report a de novo design study driven by synthetic tractability and aimed at the multi-objective prioritization of computer-generated 5-HT2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative Gaussian process bioactivity models we designed and synthesized structurally novel, selective, nanomolar and ligand-efficient 5-HT2B modulators. Cellular drug-target engagement revealed remarkable accuracy of the in silico prediction models. Our results suggest that a seamless amalgamation of computational activity prediction and microfluidics-assisted synthesis is suitable for the automated de novo design of small molecules with designer polypharmacology.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45


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