A validation study on the practical use of automated de novo design

The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 2002-07, Vol.16 (7), p.459-478
Main Authors: Stahl, Martin, Todorov, Nikolay P, James, Tim, Mauser, Harald, Boehm, Hans-Joachim, Dean, Philip M
Format: Article
Language:English
Subjects:
Algorithms
Automation
Design
Drug Design
Enzyme Inhibitors - chemistry
Models, Molecular
Validation studies
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Summary:The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the maximum common substructure of two small molecules. It is shown that the Skelgen algorithm generates representatives of many inhibitor classes within a very short time and that the new similarity measure is useful for comparing and clustering designed structures. The results demonstrate the necessity of properly defining search constraints in practical applications of de novo design.
ISSN:0920-654X
1573-4951
DOI:10.1023/A:1021242018286