Phosphoinositide-3-kinases (PI3Ks): Combined Comparative Modeling and 3D-QSAR To Rationalize the Inhibition of p110

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• 作者：Raphaë ; l Fr&eacute ; d&eacute ; rick ; William A. Denny
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：48
• 期：3
• 页码：629 - 638
• 全文大小：889K
• 年卷期：v.48,no.3(March 2008)
• ISSN：1549-960X

文摘

The p110DER=0> isoform of the class IA PI3Ks was recently genetically validated as a promising target foranticancer therapy. However, up to now, only one compound (PIK75 = 1) has been reported as a verypotent and selective inhibitor of this isoform. The lack of a 3D structure for this enzyme has clearly hinderedthe discovery of new p110 selective compounds. In view of this, we combined target-based (homologymodeling) and ligand-based (3D-QSAR) approaches in an attempt to define an integrated interaction modelfor p110 inhibition. Twenty-five analogues of 1 were docked within the putative p110 binding site, andthe 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 analyzedusing a challenging test set of 5 compounds. CoMSIA, and particularly CoMFA, models were found tooutperform the other methods, predicting accurately the potency of 100% of the compounds in the test set,thereby validating our p110 homology model for use in further drug development.