White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets

Baurin, N., Aboul-Ela, F., Barril, X., Davis, B., Drysdale, M., Dymock, B., Finch, H., Fromont, C., Richardson, C., Simmonite, H. and Hubbard, R.E. (2004) Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets. Journal of Chemical Information and Modelling, 44 (6). pp. 2157-2166. ISSN 1549-9596

Full text not available from this repository.

Abstract

We have designed four generations of a low molecular weight fragment library for use in NMR-based screening against protein targets. The library initially contained 723 fragments which were selected manually from the Available Chemicals Directory. A series of in silico filters and property calculations were developed to automate the selection process, allowing a larger database of 1.79M available compounds to be searched for a further 357 compounds that were added to the library. A kinase binding pharmacophore was then derived to select 174 kinase-focused fragments. Finally, an additional 61 fragments were selected to increase the number of different pharmacophores represented within the library. All of the fragments added to the library passed quality checks to ensure they were suitable for the screening protocol, with appropriate solubility, purity, chemical stability, and unambiguous NMR spectrum. The successive generations of libraries have been characterized through analysis of structural properties (molecular weight, lipophilicity, polar surface area, number of rotatable bonds, and hydrogen-bonding potential) and by analyzing their pharmacophoric complexity. These calculations have been used to compare the fragment libraries with a drug-like reference set of compounds and a set of molecules that bind to protein active sites. In addition, an analysis of the overall results of screening the library against the ATP binding site of two protein targets (HSP90 and CDK2) reveals different patterns of fragment binding, demonstrating that the approach can find selective compounds that discriminate between related binding sites.

Item Type: Article
Institution: The University of York
Academic Units: The University of York > Chemistry (York)
Depositing User: York RAE Import
Date Deposited: 24 Apr 2009 10:43
Last Modified: 24 Apr 2009 10:43
Published Version: http://dx.doi.org/10.1021/ci049806z
Status: Published
Publisher: American Chemical Society
Identification Number: 10.1021/ci049806z
URI: http://eprints.whiterose.ac.uk/id/eprint/6559

Actions (repository staff only: login required)