title: Structure-activity relationships study of mTOR kinase inhibition using QSAR and structure-based drug design approaches.
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 ofr2=0.799 and a cross-validation ofq2=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.
authors.affiliation: Biotechnology Laboratory (Medbiotech), Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Rabat, Morroco.
authors.forename: Wiame
authors.initials: W
authors.lastname: Lakhlili
authors.affiliation: OribasePharma, Montpellier, France.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Yasri
authors.affiliation: Biotechnology Laboratory (Medbiotech), Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Rabat, Morroco.
authors.forename: Azeddine
authors.initials: A
authors.lastname: Ibrahimi
keywords: PLS; docking; mTOR inhibitors; partial least square; quantitative structureactivity relationship