title: Second-generation de novo design: a view from a medicinal chemist perspective.
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.
authors: Center for Bioinformatics, University of Hamburg, Bundesstrasse 43, 20146, Hamburg, Germany. zaliani@zbh.uni-hamburg.de
authors: Andrea
authors: A
authors: Zaliani
authors: Krisztina
authors: K
authors: Boda
authors: Thomas
authors: T
authors: Seidel
authors: Achim
authors: A
authors: Herwig
authors: Christof H
authors: CH
authors: Schwab
authors: Johann
authors: J
authors: Gasteiger
authors: Holger
authors: H
authors: Claussen
authors: Christian
authors: C
authors: Lemmen
authors: Jörg
authors: J
authors: Degen
authors: Juri
authors: J
authors: Pärn
authors: Matthias
authors: M
authors: Rarey
mesh_terms: D000465:Algorithms; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries