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PLoS Comput Biol. 2012;8(2):e1002380. doi: 10.1371/journal.pcbi.1002380. Epub 2012 Feb 16.

DOGS: reaction-driven de novo design of bioactive compounds.

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1
Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zürich, Switzerland.

Abstract

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.

PMID:
22359493
PMCID:
PMC3280956
DOI:
10.1371/journal.pcbi.1002380
[Indexed for MEDLINE]
Free PMC Article
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