Second-generation de novo design: a view from a medicinal chemist perspective
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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.
KeywordsStructure-based de novo design NovoBench Fragment space Validation study Synthetic accessibility Feature Trees FragView FlexNovo SYLVIA
The authors thank the editor and the reviewers for their substantial help as well as all partners in the NovoBench Project for fruitful discussions and feedback. They also are grateful to Viola Hingst for carefully reviewing the paper and, finally, they acknowledge the German Ministry of Education and Research for funding (Grant 313324A).
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