TY  - JOUR
A1  - Hartenfeller, Markus
A1  - Zettl, Heiko
A1  - Walter, Miriam
A1  - Rupp, Matthias
A1  - Reisen, Felix
A1  - Proschak, Ewgenij
A1  - Weggen, Sascha
A1  - Stark, Holger
A1  - Schneider, Gisbert
T1  - DOGS: reaction-driven de novo design of bioactive compounds
T2  - PLoS Computational Biology
N2  - 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.
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/24617
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-246179
SN  - 1553-7358
SN  - 1553-734X
VL  - 8
IS  - 2: e1002380
PB  - Public Library of Science
CY  - San Francisco, Calif.
ER  -