Elaborate ligand-based modeling coupled with multiple linear regression and k nearest neighbor QSAR analyses unveiled new nanomolar mTOR inhibitors.
The mammalian target of rapamycin (mTOR) has an important role in cell growth, proliferation, and survival. mTOR is frequently hyperactivated in cancer, and therefore, it is a clinically validated target for cancer therapy. In this study, we combined exhaustive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent mTOR inhibitors employing 210 known mTOR ligands. Genetic function algorithm (GFA) coupled with k nearest neighbor (kNN) and multiple linear regression (MLR) analyses were employed to build self-consistent and predictive QSAR models based on optimal combinations of pharmacophores and physicochemical descriptors. Successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve (ROC) profiles. Optimal QSAR models and their associated pharmacophore hypotheses were validated by identification and experimental evaluation of several new promising mTOR inhibitory leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hit illustrated an IC50 value of 48 nM.
Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan , Amman 11942, Jordan.
Mohammad A
MA
Khanfar
Mutasem O
MO
Taha
D000465:Algorithms; D001499:Bayes Theorem; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D062126:Databases, Chemical; D055808:Drug Discovery; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008024:Ligands; D016014:Linear Models; D008956:Models, Chemical; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*
D008024:Ligands; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D058544:Class Ib Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases