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Analysis of neighborhood behavior in lead optimization and array design

Papadatos, G., Cooper, A.W.J., Kadirkamanathan, V., Macdonald, S.J.F., McLay, I.M., Pickett, S.D., Pritchard, J.M., Willett, P. and Gillet, V.J. (2009) Analysis of neighborhood behavior in lead optimization and array design. Journal of Chemical Information and Modeling, 49 (2). pp. 195-208. ISSN 1549-9596

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Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.

Item Type: Article
Institution: The University of Sheffield
Academic Units: The University of Sheffield > Faculty of Social Sciences (Sheffield) > Information School (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 29 Sep 2009 09:32
Last Modified: 29 Sep 2009 17:46
Published Version: http://dx.doi.org/10.1021/ci800302g
Status: Published
Publisher: American Chemical Society
Identification Number: 10.1021/ci800302g
URI: http://eprints.whiterose.ac.uk/id/eprint/9790

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