title: Multi-objective molecular de novo design by adaptive fragment prioritization.
abstract: We present the development and application of a computational molecular de novo design method for obtaining bioactive compounds with desired on- and off-target binding. The approach translates the nature-inspired concept of ant colony optimization to combinatorial building block selection. By relying on publicly available structure-activity data, we developed a predictive quantitative polypharmacology model for 640 human drug targets. By taking reductive amination as an example of a privileged reaction, we obtained novel subtype-selective and multitarget-modulating dopamine D4 antagonists, as well as ligands selective for the sigma-1 receptor with accurately predicted affinities. The nanomolar potencies of the hits obtained, their high ligand efficiencies, and an overall success rate of 90 % demonstrate that this ligand-based computer-aided molecular design method may guide target-focused combinatorial chemistry.
authors.affiliation: Eidgenössische Technische Hochschule (ETH), Departement Chemie und Angewandte Biowissenschaften, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
authors.forename: Michael
authors.initials: M
authors.lastname: Reutlinger
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Petra
authors.initials: P
authors.lastname: Schneider
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
keywords: GPCR; computer-assisted drug design; machine learning; polypharmacology; reductive amination