Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12779/5606
Title: Docking, 3D-QSAR studies and in silicoADME prediction on c-Src tyrosine kinase inhibitors
Authors: Tintori, Cristina
Magnani, Matteo
S., Schenone
Botta, Maurizio 
Issue Date: 2009
Project: None 
Journal: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Abstract: 
Docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis were performed on a wide set of c-Src inhibitors. The study was conducted using a structure-based alignment and by applying the GRID/GOLPE approach. The present 3D-QSAR investigation proved to be of good statistical value, displaying r(2), q(2) and cross-validation SDEP values of 0.94, 0.84 and 0.42, respectively. Moreover, such a model also proved to be capable of predicting the activities of an external test set of compounds. The availability of the 3D structure of the target made possible the interpretation of steric and electrostatic maps within the binding site environment and provided useful insight into the structural requirements for inhibitory activity against c-Src. Two regions whose occupation by hydrophobic portions of ligands would favourably affect the activity were clearly identified. Moreover, hydrogen bond interactions involving residues Met343, Asp406 and Ser347 emerged as playing a key role in determining the affinity of the active inhibitors toward c-Src. Furthermore, the inhibitors bearing a basic nitrogen provided enhanced potency through protonation and salt bridge formation with Asp350. A preliminary pharmacokinetic profile of the molecules under analysis was also drawn on the basis of Volsurf predictions.
Description: 
22246
URI: http://hdl.handle.net/20.500.12779/5606
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2008.07.002
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