Structure-based Drug Design Approaches Disclose Natural Molecules as Potential Cancer Immunotherapeutics via Modulation of HA2AR Receptor

HA2AR is a membrane receptor that exemplifies an important pathophysiological mediator in the development of multiple illnesses including cancer. The recent scientific literature supports the therapeutic significance of HA2AR targeting for cancer chemotherapy due to the established role of HA2AR as an immune check blocker that facilitates the immune escape of the tumor in hypoxic environments. In this study, we have been focused on harnessing integral ensembles of computational chemistry to screen natural compounds from the SN3 database in search of potential immunotherapeutics via HA2AR inhibition. This includes structure-based pharmacophore modeling, molecular docking, MM/GBSA calculations, and molecular dynamic simulation. Upon the Phase screening, 2965 compounds that matched the developed hypothesis have been subjected to HTVS and XP docking analysis. Three SN3 molecules; SN0259126, SN0296460, and SN0355465, outpaced the docking score of ZM241385, the A2A known co-crystalized inhibitor. The rescoring of these hits through MM/GBSA calculations disclosed intriguing binding free energies, particularly for SN0355465; ∆G equals -70.57kcal/mol. To decisively demonstrate the robustness of these results, HA2AR in complex with each of the four compounds; ZM241385, SN0259126, SN0296460, and SN0355465, have been subjected to MD simulations for 100 nanoseconds. RMSD, RMSF, and protein-ligand contacts histograms foretold durable interaction patterns with no major fluctuations in alpha carbon of HA2AR. These results protrude three natural compounds as prospective immunotherapeutics with a remarkable tendency to repressively tackle HA2AR which would construct new avenues in the perception of adenosine receptors and their corresponding clinical utility in cancer treatment.