Generation of Non-Nucleotide CD73 Inhibitors Using a Molecular Docking and 3D-QSAR Approach

Radiotherapy and chemotherapy are conventional cancer treatments. Around 60% of all patients who are diagnosed with cancer receive radio- or chemotherapy in combination with surgery during their disease. Only a few patients respond to the blockage of immune checkpoints alone, or in combination therapy, because their tumours might not be immunogenic. Under these circumstances, an increasing level of extracellular adenosine via the activation of ecto-5'-nucleotidase (CD73) and consequent adenosine receptor signalling is a typical mechanism that tumours use to evade immune surveillance. CD73 is responsible for the conversion of adenosine monophosphate to adenosine. CD73 is overexpressed in various tumour types. Hence, targetting CD73's signalling is important for the reversal of adenosine-facilitated immune suppression. In this study, we selected a potent series of the non-nucleotide small molecule inhibitors of CD73. Molecular docking studies were performed in order to examine the binding mode of the inhibitors inside the active site of CD73 and 3D-QSAR was used to study the structure-activity relationship. The obtained CoMFA (q(2) = 0.844, ONC = 5, r(2) = 0.947) and CoMSIA (q(2) = 0.804, ONC = 4, r(2) = 0.954) models showed reasonable statistical values. The 3D-QSAR contour map analysis revealed useful structural characteristics that were needed to modify non-nucleotide small molecule inhibitors. We used the structural information from the overall docking and 3D-QSAR results to design new, potent CD73 non-nucleotide inhibitors. The newly designed CD73 inhibitors exhibited higher activity (predicted pIC(50)) than the most active compound of all of the derivatives that were selected for this study. Further experimental studies are needed in order to validate the new CD73 inhibitors.

Automated summary

Radiotherapy and chemotherapy are standard cancer treatments used in combination with surgery for around 60% of cancer patients. Only a few patients respond to immune checkpoint blockage due to low tumor immunogenicity, with tumor cells often evading immune surveillance through CD73 signaling and extracellular adenosine production. In this study, non-nucleotide small molecule inhibitors targeting CD73 were designed using molecular docking and 3D-QSAR studies, showing promising activity compared to existing compounds. Further experimental validation of these new inhibitors is required.