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Multidimensional De Novo Design Reveals 5‐HT 2B Receptor‐Selective Ligands
Author(s) -
Rodrigues Tiago,
Hauser Nadine,
Reker Daniel,
Reutlinger Michael,
Wunderlin Tiffany,
Hamon Jacques,
Koch Guido,
Schneider Gisbert
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201410201
Subject(s) - prioritization , binding affinities , ligand (biochemistry) , combinatorial chemistry , computational biology , small molecule , chemistry , computer science , microfluidics , nanotechnology , receptor , biology , materials science , biochemistry , engineering , management science
We report a multi‐objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer‐generated 5‐HT 2B 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‐HT 2B 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.