dogs reaction-driven de novo design of bioactive compounds狗reaction-driven新创生物活性化合物的设计.pdfVIP

DOGS: Reaction-Driven de novo Design of Bioactive Compounds 1 1 2 1 1 2 Markus Hartenfeller , Heiko Zettl , Miriam Walter , Matthias Rupp , Felix Reisen , Ewgenij Proschak , 3 2 1 Sascha Weggen , Holger Stark , Gisbert Schneider * ¨ 1 Swiss Federal Institute of Technology (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zurich, Switzerland, 2 Goethe- ¨ University, Institute of Pharmaceutical Chemistry, LiFF/OSF/ZAFES, Frankfurt am Main, Germany, 3 Department of Neuropathology, Heinrich-Heine-University, Dusseldorf, Germany 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