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

Author(s): Ishan I. Panchal*, Sandip N. Badeliya, Rakesh Patel, Ashish Patel, Animesh Devaligar

Journal Name: Current Drug Discovery Technologies

Volume 16 , Issue 3 , 2019

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Graphical Abstract:


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.

Keywords: mTORC1/ PI3K, sapanisertib, dactolisib, molinspiration, in silico, mTOR.

Burstein HJ. The distinctive nature of HER2-positive breast cancers. The New Engl J Med 2005; 353(16): 1652-4.
Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet 2008; 102(2): 128-31.
Buza N, Roque DM, Santin AD. HER2/neu in endometrial cancer: a promising therapeutic target with diagnostic challenges. Arch of Patho & Labo Med 2014; 138(3): 343-50.
Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C. Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy. J Micro 2011; 242(1): 46-54.
Madarnas Y, Trudeau M, Franek JA, McCready D, Pritchard KI, Messersmith H. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: A systematic review. Cancer Treat Rev 2008; 34(6): 539-57.
Mariani G, Fasolo A, De Benedictis E, Gianni L. Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat Clin Pract Oncol 2009; 6(2): 93-104.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353(16): 1659-72.
Sutherlin DP, Sampath D, Berry M, Castanedo G, Chang Z, Chuckowree I. Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available Pan-PI3-Kinase and dual Pan-PI3-Kinase/mTOR inhibitors for the treatment of cancer. J Med Chem 2010; 53: 1086-97.
Tomoyasu I, Masaki S, Hiroshi B, et al. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2) /epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo [3,2-d] pyrimidine scaffold. J Med Chem 2011; 54: 8030-50.
Ishan P, Dhrubo JS, Ashish S, Ashish P, Vashisth B. Molecular docking and synthesis of some substituted sulphonylurea/pyrrolidine -based derivatives as hypoglycemic agents. J Chem Pharm Res 2017; 9(8): 164-72.

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Article Details

Year: 2019
Published on: 14 October, 2019
Page: [297 - 306]
Pages: 10
DOI: 10.2174/1568009618666181102144934
Price: $65

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