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Molecular Modeling Studies of Urea-morpholinopyrimidine Analogues as Dual Inhibitors of mTORC1 and mTORC2 Using 3D-QSAR, Topomer CoMFA and Molecular Docking Simulations

[ Vol. 15 , Issue. 10 ]

Author(s):

Xiaodong Gao, Yujie Ren*, Jianqing Huang and Anjian Pan   Pages 1026 - 1035 ( 10 )

Abstract:


Background: PI3K/Akt/mTOR was an important signal transduction pathway, activated in tumor cells. The dual inhibitors of mTORC1 and mTORC2 could suppress the tumor growth and angiogenesis by inhibiting the abnormal signal pathway. To deeply understand the structure-activity relationship of urea-morpholinopyrimidine analogues as inhibitors of mTOR, molecular modeling studies include Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) and molecular docking was carried out.

Methods: CoMFA CoMSIA and Topomer CoMFA methods created by 3D-QSAR were used to build stable model, and significant correlation coefficients for dual inhibitors (q2 = 0.750, r2 = 0.931 for CoMFA model; q2 = 0.745, r2 = 0.927 for CoMSIA model; q2 = 0.780, r2 = 0.950 for Topomer CoMFA model) were obtained. At the same time, the generated models were validated using the test sets (external predictive correlation coefficient rpred 2 = 0.696 for CoMFA; rpred 2 = 0.794 for CoMSIA).

Result: These correlation coefficients confirmed that these models were correct and could be used to predict new compounds. Afterward, molecular docking study was performed to study the molecular interactions between these analogues and the receptor protein.

Conclusion: In this study, the selected urea-morpholinopyrimidine compounds were docking into the active site. Some key amino acid residues such as Lys802, Ser806, Lys808 and Val882 were determined. The satisfactory results from this study may aid in the research and can be used to design novel dual inhibitors.

Keywords:

Dual inhibitor, mTOR, CoMFA, CoMSIA, topomer CoMFA, molecular docking simulations.

Affiliation:

School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai

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