Binding conformations, QSAR, and molecular design of Alkene‐3‐quinolinecarbonitriles as Src inhibitors. Issue 10 (29th October 2012)

• Record Type: Journal Article
• Authors: Zeng, G. H.; Fang, D. Q.; Wu, W. J.; Zhang, R.; Xie, W. G.; Wu, J. H.; Shen, Y.
• Is Part Of: International journal of quantum chemistry. Volume 113:Issue 10(2013:May 15)
• Page Start: 1467
• Page End: 1478
• Publication Date: 2012-10-29
• Subjects: Quantum chemistry -- Periodicals; 541.28
• DOI: 10.1002/qua.24344
• Languages: English
• ISSNs: 0020-7608

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A theoretical study on binding orientations and quantitative structure–activity relationship (QSAR) of a novel series of alkene‐3‐quinolinecarbonitriles acting as Src inhibitors has been carried out by using the docking study and three‐dimensional QSAR (3D‐QSAR) analyses. The appropriate binding orientations and conformations of these compounds interacting with Src kinase were revealed by the docking studies, and the established 3D‐QSAR models show significant statistical quality and satisfactory predictive ability, with high <italic>R</italic><sup>2</sup> values and <italic>q</italic><sup>2</sup> values: comparative molecular field analysis (CoMFA) model (<italic>q</italic><sup>2</sup> = 0.748, <italic>R</italic><sup>2</sup> = 0.972), comparative molecular similarity indices analysis (CoMSIA) model (<italic>q</italic><sup>2</sup> = 0.731, <italic>R</italic><sup>2</sup> = 0.987). The systemic external validation indicated that both CoMFA and CoMSIA models possessed high predictive powers with <tex-math notation="tex"><![CDATA[$ R{^2}_{\!\!\!\rm pred} $]]></tex-math><inline-graphic xlink:href="ark:/27927/pgg1x72j761" mimetype="image" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> values of 0.818 and 0.892, <tex-math notation="tex"><![CDATA[$ {r^2}_{\!\!\!\rm m} $]]></tex-math><inline-graphic xlink:href="ark:/27927/pgg1x72j784" mimetype="image" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> values of 0.879 and 0.886, <tex-math notation="tex"><![CDATA[$ {r^2}_{\!\!\!\rm m(LOO)} $]]></tex-math><inline-graphic xlink:href="ark:/27927/pgg1x72j77k" mimetype="image" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> values of 0.874 and 0.874, <tex-math notation="tex"><![CDATA[$ r^2_{\rm m(overall)} $]]></tex-math><inline-graphic xlink:href="ark:/27927/pgg1x72j73c" mimetype="image" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> values of 0.879 and 0.885, respectively. Several key structural features of the compounds responsible for inhibitory activity were discussed in detail. Based on these structural factors, eight new compounds with quite higher predicted Src‐inhibitory activities have been designed and presented. We hope these theoretical results can offer some valuable references for the pharmaceutical molecular design as well as the action mechanism analysis. © 2012 Wiley Periodicals, Inc.</p> </abstract>