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J Med Chem. 2009 Feb 26;52(4):964-75. doi: 10.1021/jm800829v.

Computational studies of epidermal growth factor receptor: docking reliability, three-dimensional quantitative structure-activity relationship analysis, and virtual screening studies.

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Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.


An aberrant activity of the epidermal growth factor receptor (EGFR) has been shown to be related to many human cancers, such as breast and liver cancers, thus making EGFR an attractive target for antitumor drug discovery. In this study we evaluated the reliability of various kinds of docking software and procedures to predict the binding disposition of EGFR inhibitors. By application of the best procedure and use of more than 200 compounds, a receptor-based 3D-QSAR model for EGFR inhibition was developed. On the basis of the results obtained, the possibility of developing virtual screening studies was also evaluated. The VS procedure that proved to be the most reliable from a computational point of view was then used to filter the Maybridge database in order to identify new EGFR inhibitors. Enzymatic assays revealed that among the eight top-scoring compounds, seven proved to inhibit EGFR activity at a concentration of 100 microM, two of them exhibiting IC(50) values in the low micromolar range and one in the nanomolar range. These results demonstrate the validity of the methodologies followed. Furthermore, the two low micromolar compounds may be considered as very interesting leads for the development of new EGFR inhibitors.

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