Cipargamin could inhibit human adenosine receptor A3 with higher binding affinity than Plasmodium falciparum P-type ATPase 4: An In silico study

Abstract

Aim: This study aimed to predict the molecular targets of cipargamin in humans and estimate the structural dynamics and binding affinity of their interactions compared to that of Plasmodium falciparum P-type ATPase 4 (PfATP4). Methods: In silico methods were used in this study which include target prediction, structure modeling and dynamics, and molecular docking. Results: The results showed that cipargamin had 100% probability of binding to the human adenosine A3 receptor (ADORA3) and about 15% for other human targets which include tyrosine-protein kinase JAK2, adenosine A2a receptor, phosphodiesterase 5A and cathepsin K. The results of molecular docking showed that binding energy of cipargamin to PfATP4 and hADORA3 were-12.40 kcal/mol-1 and-13.40 kcal/mol-1 respectively. The docking was validated by the binding of enprofylline and fostamatinib to PfATP4 and hADORA3. Overall, the binding of cipargamin was closely similar to that of fostamatinib. This study shows the potential of cipargamin to modulate the activities of PfATP4 of the parasite (P. falciparum) as well as ADORA3 of the host (Homo sapiens). Conclusion: All the previous studies of cirpagamin have not implicated its action on hADORA3, thus this study provides an insight into a possible role of hADORA3 in the mechanism of malarial infection.