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Article

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

by 1,2 and 1,2,*
1
College of Pharmacy, Hanyang University, Ansan 426-791, Korea
2
Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Bono Lučić
Int. J. Mol. Sci. 2021, 22(23), 12745; https://doi.org/10.3390/ijms222312745
Received: 8 November 2021 / Revised: 23 November 2021 / Accepted: 23 November 2021 / Published: 25 November 2021
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 (q2 = 0.844, ONC = 5, r2 = 0.947) and CoMSIA (q2 = 0.804, ONC = 4, r2 = 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 pIC50) 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. View Full-Text
Keywords: chemotherapy; cancer; CD73; molecular docking; CoMFA; CoMSIA; 3D-QSAR; inhibitors chemotherapy; cancer; CD73; molecular docking; CoMFA; CoMSIA; 3D-QSAR; inhibitors
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MDPI and ACS Style

Bhujbal, S.P.; Hah, J.-M. Generation of Non-Nucleotide CD73 Inhibitors Using a Molecular Docking and 3D-QSAR Approach. Int. J. Mol. Sci. 2021, 22, 12745. https://doi.org/10.3390/ijms222312745

AMA Style

Bhujbal SP, Hah J-M. Generation of Non-Nucleotide CD73 Inhibitors Using a Molecular Docking and 3D-QSAR Approach. International Journal of Molecular Sciences. 2021; 22(23):12745. https://doi.org/10.3390/ijms222312745

Chicago/Turabian Style

Bhujbal, Swapnil P., and Jung-Mi Hah. 2021. "Generation of Non-Nucleotide CD73 Inhibitors Using a Molecular Docking and 3D-QSAR Approach" International Journal of Molecular Sciences 22, no. 23: 12745. https://doi.org/10.3390/ijms222312745

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