Phosphoinositide-3-kinases (PI3Ks): Combined comparative modeling and 3D-QSAR to rationalize the inhibition of p110±.

Show simple item record Frederick, R en Denny, William en 2011-11-17T17:24:35Z en 2008 en
dc.identifier.citation Journal of Chemical Information and Modeling 48(3):629-638 2008 en
dc.identifier.issn 1549-9596 en
dc.identifier.uri en
dc.description.abstract The p110α isoform of the class IA PI3Ks was recently genetically validated as a promising target for anticancer therapy. However, up to now, only one compound (PIK75 = 1) has been reported as a very potent and selective inhibitor of this isoform. The lack of a 3D structure for this enzyme has clearly hindered the discovery of new p110α selective compounds. In view of this, we combined target-based (homology modeling) and ligand-based (3D-QSAR) approaches in an attempt to define an integrated interaction model for p110α inhibition. Twenty-five analogues of 1 were docked within the putative p110α binding site, and the molecular alignment generated was subsequently used to derive QSAR models based on scoring function, free energy of binding, CoMFA. and CoMSIA. The predictive power of these models was then analyzed using a challenging test set of 5 compounds. CoMSIA, and particularly CoMFA, models were found to outperform the other methods, predicting accurately the potency of 100% of the compounds in the test set, thereby validating our p110α homology model for use in further drug development. en
dc.language EN en
dc.publisher American Chemical Society en
dc.relation.ispartofseries Journal of Chemical Information and Modeling en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
dc.rights.uri en
dc.subject 3-KINASE en
dc.subject DERIVATIVES en
dc.subject KINASE en
dc.subject INSIGHTS en
dc.subject PATHWAY en
dc.subject GROWTH en
dc.title Phosphoinositide-3-kinases (PI3Ks): Combined comparative modeling and 3D-QSAR to rationalize the inhibition of p110±. en
dc.type Journal Article en
dc.identifier.doi 10.1021/ci700348m en
pubs.issue 3 en
pubs.begin-page 629 en
pubs.volume 48 en
dc.rights.holder Copyright: American Chemical Society en
dc.identifier.pmid 18275176 en
pubs.end-page 638 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 79522 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 18275176 en

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