Paper Info
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.
Year
DOI
Venue
2009
10.1007/s10822-009-9291-2
Journal of computer-aided molecular design
Keywords
Field
DocType
Structure-based de novo design,NovoBench,Fragment space,Validation study,Synthetic accessibility,Feature Trees,FragView,FlexNovo,SYLVIA
Suite,Ranking,Computer science,Bioinformatics,Chemist,Workflow
Journal
Volume
Issue
ISSN
23
8
1573-4951
Citations 
PageRank 
References 
5
0.41
7
Authors
11
Name
Order
Citations
PageRank
Andrea Zaliani16210.45
Krisztina Boda2232.03
Thomas Seidel3263.92
Achim Herwig4141.50
Christof H Schwab5161.89
Johann Gasteiger653085.24
Holger Claussen71575183.63
Christian Lemmen821722.28
Jörg Degen961.13
Juri Pärn1060.80
Matthias Rarey1147276.58