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 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.

Molecular screening and docking analysis of LMTK3 and AKT1 combined inhibitors

“…The predictive performances of this model were represented by cross-validated RMSE with 0.66699, and cross-validated R2 with 0.69958.The QSAR model of AKT1 protein validated was used to filter a set of 100 chemical structures, extracted from the DockBlaster server. We selected 74 compounds with activity predictive value greater than 6 14.…”

The Role of Organic Small Molecules in Pain Management

“…QSAR modeling is the most used and powerful approach that allows correlating chemical modifications in a molecule with its biological activity [ 69 ]. This approach has been applied to find new treatments for Alzheimer’s disease [ 70 ], malaria [ 71 , 72 ], diabetes [ 73 , 74 ], cancer [ 75 , 76 , 77 ], and HIV [ 78 ]. Based on the anti-inflammatory activity of pyrazolo[1,5-a]pyrimidine, 2,5-diarylpyrazolo[1,5-a]pyrimidin-7-amines, new compounds were synthesized.…”

Virtual docking screening and QSAR studies to explore AKT and mTOR inhibitors acting on PI3K in cancers

“…The grid boxes were set to have between 16 and 20Å of edge with coordinates x = 19.698, y = 62.891, z = 20.837. The coordinates were determined using the potential substrate binding residues as centroids (in the hinge region and the activation loop) [19].…”