Computational Investigation of Adenosine 5′- (α, β-methylene)- diphosphate (AMPCP) Derivatives as Ecto-5′-nucleotidase (CD73) Inhibitors by Using 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulations

CD73, as a surface enzyme anchored on the outside of the cell membrane via glycosylphosphatidylinositol (GPI), can convert the AMP in the tumor cell microenvironment into adenosine to promote the growth of tumor cells. It has been overexpressed in many different types of human tumors, such as gastric cancer, pancreatic cancer, liver cancer and other tumor cells. Therefore, targeted inhibitors of CD73 are considered as potential tumor treatment methods. Due to the low bioavailability of nucleoside CD73 inhibitors, it is necessary to develop new inhibitors. In this study, through molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular dynamics (MD) simulations, a series of CD73 inhibitors were calculated and studied to reveal their structure-activity relationships. Through molecular docking studies, explore the possible mode of interaction between inhibitors and protein. Subsequently, a 3D-QSAR model was established by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q 2 and R 2 values ​​are 0.708 and 0.983, respectively, while for the best CoMSIA model, the Q 2 and R 2 values ​​are 0.809 and 0.992, respectively. In addition, the stability of the complex formed by the two inhibitors and CD73 was evaluated by molecular dynamics simulation, and the results are consistent with the results of molecular docking and 3D-QSAR research. Finally, the binding free energy was calculated by the surface area method (MM-GBSA), and the results are consistent with the activities that Van Der Waals and Coulomb contribute the most during the binding process of the molecule to the CD73 protein. In conclusion, our research provides valuable information for the further development of CD73 inhibitors.