Abstract
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 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, the possible mode of interaction between inhibitors and protein is explored. 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 Q2 and R2 values are 0.708 and 0.983, respectively, while for the best CoMSIA model, the Q2 and R2 values are 0.809 and 0.992, respectively. Based on the contour maps, we designed ten new CD73 inhibitors and predicted their activity by the model, all of them are better than molecules in the dataset. In addition, in order to select potential drug candidates, ADMET prediction was performed on template molecules and designed compounds. Moreover, 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.
Highlights
As a new method, immune checkpoint inhibitors (ICIs) have caused a revolutionary cancer treatment [1]
The root mean square deviation (RMSD)between the native conformation and the redocked conformation was 0.483 Å, which indicates that the XP algorithm in Glide was reliable, and it can be considered that this algorithm can be used for subsequent molecular docking studies
The compounds in our dataset were derived from four types, including partial compounds obtained by substituting AMPCP as the skeleton and three skeletons obtained by substituting its adenine with different nitrogen heterocycles such as: pyrazolopyrimidine, pyrrolopyrimidine, pyrazolopyridine
Summary
Immune checkpoint inhibitors (ICIs) have caused a revolutionary cancer treatment [1]. CD39 is a cell surface enzyme, which is highly expressed in tumor cells, exhausted T cells and multi-inhibitory cells [3, 4]. It is a key enzyme for the hydrolysis of ATP and ADP into AMP [5]. CD73 acts as a signal and adhesion molecule, which can regulate the interaction between cells and extracellular matrix components (such as laminin and fibronectin) to mediate the invasion and metastasis characteristics of cancer [13] targeted therapy that inhibits CD73 is expected to be a new immunotherapy method
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