Second-generation de novo design: a view from a medicinal chemist perspective |
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Authors: | Andrea Zaliani Krisztina Boda Thomas Seidel Achim Herwig Christof H Schwab Johann Gasteiger Holger Claußen Christian Lemmen Jörg Degen Juri Pärn Matthias Rarey |
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Institution: | (1) Center for Bioinformatics, University of Hamburg, Bundesstrasse 43, 20146 Hamburg, Germany;(2) Present address: Nycomed GmbH, Byk-Guldenstr 2, 78467 Constance, Germany;(3) Computer-Chemie-Centrum, University Erlangen-Nürnberg, Naegelsbachstrasse 25, 91052 Erlangen, Germany;(4) Molecular Networks GmbH, Henkestrasse 91, 91052 Erlangen, Germany;(5) BioSolveIT GmbH, An der Ziegelei 75, 53757 Sankt Augustin, Germany |
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Abstract: | For computational de novo design, a general retrospective validation work is a very challenging task. Here we propose a comprehensive
workflow to de novo design driven by the needs of computational and medicinal chemists and, at the same time, we propose a
general validation scheme for this technique. The study was conducted combining a suite of already published programs developed
within the framework of the NovoBench project, which involved three different pharmaceutical companies and four groups of
developers. Based on 188 PDB protein–ligand complexes with diverse functions, the study involved the ligand reconstruction
by means of a fragment-based de-novo design approach. The structure-based de novo search engine FlexNovo showed in five out
of eight total cases the ability to reconstruct native ligands and to rank them in four cases out of five within the first
five candidates. The generated structures were ranked according to their synthetic accessibilities evaluated by the program
SYLVIA. This investigation showed that the final candidate molecules have about the same synthetic complexity as the respective
reference ligands. Furthermore, the plausibility of being true actives was assessed through literature searches.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
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Keywords: | Structure-based de novo design NovoBench Fragment space Validation study Synthetic accessibility Feature Trees FragView FlexNovo SYLVIA |
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