Evaluation of a Novel Shape-Based Computational Filter for Lead Evolution:  Application to Thrombin Inhibitors

A novel shape−feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that ar...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-06, Vol.45 (12), p.2494-2500
Main Authors: Srinivasan, Jayashree, Castellino, Angelo, Bradley, Erin K, Eksterowicz, John E, Grootenhuis, Peter D. J, Putta, Santosh, Stanton, Robert V
Format: Article
Language:English
Subjects:
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Combinatorial Chemistry Techniques
Crystallography, X-Ray
Databases, Factual
Humans
Ligands
Medical sciences
Models, Molecular
Molecular Conformation
Pharmacology. Drug treatments
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - chemistry
Structure-Activity Relationship
Thrombin - antagonists & inhibitors
Thrombin - chemistry
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Summary:A novel shape−feature-based computational method is described and used to rapidly filter compound libraries. The computational model, built using three-dimensional conformations of active and inactive molecules, consists of a collection of whole molecule shapes and chemical feature positions that are ranked according to their correlation with activity. A small ensemble of these shapes and features is used to filter virtual compound libraries. The method is applied to two thrombin data sets and is shown to be efficient in identifying novel scaffolds with enhanced hit rates.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm010494q