Journal
PLOS COMPUTATIONAL BIOLOGY
Volume 8, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pcbi.1002380
Keywords
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Funding
- Merz Pharmaceuticals GmbH
- Lipid Signaling Forschungszentrum Frankfurt (LiFF)
- Oncogenic Signaling Frankfurt (OSF)
- EU COST [BM0806]
- Fonds der Chemischen Industrie
- DFG [MU 987/4]
- EU
- OPO Foundation Zurich
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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 H-4 receptor and gamma-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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