DOGS: reaction-driven de novo design of bioactive compounds

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of pote
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties.
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Metadaten
Author:Markus Hartenfeller, Heiko Zettl, Miriam Walter, Matthias Rupp, Felix Reisen, Ewgenij Proschak, Sascha Weggen, Holger Stark, Gisbert Schneider
URN:urn:nbn:de:hebis:30:3-246179
DOI:http://dx.doi.org/doi:10.1371/journal.pcbi.1002380
ISSN:1553-7358
ISSN:1553-734X
Parent Title (English):PLoS Computational Biology : a new community journal
Publisher:Public Library of Science
Place of publication:San Francisco, Calif.
Document Type:Article
Language:English
Date of Publication (online):2012/04/02
Date of first Publication:2012/02/16
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2012/04/02
Volume:8
Issue:2: e1002380
Pagenumber:12
HeBIS PPN:306612127
Institutes:Biochemie und Chemie
Pharmazie
Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung 3.0

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