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Structure–activity relationships study of mTOR kinase inhibition using QSAR and structure-based drug design approaches

Authors Lakhlili W, Yasri A, Ibrahimi A

Received 15 March 2016

Accepted for publication 20 September 2016

Published 2 December 2016 Volume 2016:9 Pages 7345—7353


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 6

Editor who approved publication: Dr William Cho

Wiame Lakhlili,1 Abdelaziz Yasri,2 Azeddine Ibrahimi1

Biotechnology Laboratory (Medbiotech), Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Rabat, Morroco; 2OribasePharma, Montpellier, France

Abstract: The discovery of clinically relevant inhibitors of mammalian target of rapamycin (mTOR) for anticancer therapy has proved to be a challenging task. The quantitative structure–activity relationship (QSAR) approach is a very useful and widespread technique for ligand-based drug design, which can be used to identify novel and potent mTOR inhibitors. In this study, we performed two-dimensional QSAR tests, and molecular docking validation tests of a series of mTOR ATP-competitive inhibitors to elucidate their structural properties associated with their activity. The QSAR tests were performed using partial least square method with a correlation coefficient of r2=0.799 and a cross-validation of q2=0.714. The chemical library screening was done by associating ligand-based to structure-based approach using the three-dimensional structure of mTOR developed by homology modeling. We were able to select 22 compounds from two databases as inhibitors of the mTOR kinase active site. We believe that the method and applications highlighted in this study will help future efforts toward the design of selective ATP-competitive inhibitors.

Keywords: mTOR inhibitors, quantitative structure–activity relationship, PLS, partial least square, docking

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