In silico Analysis and Molecular Docking Studies of Novel 4-Amino-3- (Isoquinolin-4-yl)-1H-Pyrazolo[3,4-d]Pyrimidine Derivatives as Dual PI3-K/mTOR Inhibitors.

Background: mTORC1/ PI3K control multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, are all important for cell and tissue growth. Sapanisertib and Dactolisib inhibit PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation.

Methods: Dactolisib contains quinolin-3-yl-2,3-dihydroimidazo[4,5-c]quinolin scaffold and Sapanisertib contains benzo[d]oxazol-5-yl-1-ethyl-1H-pyrazolo[3,4-d]pyrimidinnucleous. From the reference to both of drug novel series of 4-Amino-3-(isoquinolin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin was developed by molecular docking. In sillico analysis was done with SWISSADME online tools.

Results: Among all the designed derivatives, compounds 6(-10.6 kcal/mol) , 12( -10.7 kcal/mol), 14( -10.2 kcal/mol), and 16(-10.2 kcal/mol) have a good binding affinity than others. Biological activity was predicted by Molinspirationonline software tool showing that all compounds are active on G- protein coupled receptor. In silico toxicity profile of designed compounds was performed using the SWISSADME program, indicating that all the compounds follow the Lipinski rule of five and do not penetrate Blood brain barrier.

Conclusion: Series of pyrazolo[3,4-d]pyrimidin derivatives gives good binding affinity with pan- PI3-Kinese/Mtor inhibitors. The present study provided a better understanding of the molecular modeling requisite for maintaining and/or improving PI3K/mTOR inhibitors.