Published:
KOPS - The Institutional Repository of the University of Konstanz, 2012
Published in:PLoS Computational Biology. Public Library of Science (PLoS). 2012, 8(2), e1002380. ISSN 1553-734X. eISSN 1553-7358. Available under: doi:10.1371/journal.pcbi.1002380
Language:
English
DOI:
https://doi.org/10.1371/journal.pcbi.1002380
ISBN:
1748290606
Origination:
Footnote:
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Description:
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. ; published ; published