Flavonoids from aerial parts of Cissampelos pareira L. as antimalarial agents: Computational validation of ethnopharmacological relevance

The diverse chemical scaffolds of the Cissampelos pareira make it pharmacologically distinct because of its pleiotropic therapeutical applications. Phytochemically, C. pareira is primarily known for its isoquinoline alkaloids, but flavonoids and their glycosides have also been reported from the aerial part. Among the several traditional uses of C. pareira, the juice of leaves that are enriched with flavonoids has been used to cure malarial fever. In silico molecular docking of phytomolecules from C. pareira revealed that flavonoids exhibited good binding affinity with the selected antimalarial targets. Among the screened molecules, quercetin, quercetin-3-O-sophoroside, and kaempferol-3-O-β-D-glucuronopyranoside showed the most prominent binding with the selected Plasmodium proteins. However, quercetin-3-O-sophoroside (Q3S) showed a broad-spectrum binding affinity with falcipain-2 (-9.53 Kcal/mol), plasmepsin-2 (-12.08 Kcal/mol), Pf1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) (-14.35 Kcal/mol), Pf lactose dehydrogenase (PfLDH) (-9.57 Kcal/mol), and Pf dihydrofolate reductase (PfDHFR) (-11.62 Kcal/mol). The pharmacokinetics evaluation showed that identified hits follow several ADME-Tox properties. MD Simulation suggests that Q3S forms a highly stable complex with PfLDH. The RMSF value range of docked complexes of Q3S with Plasmepsin-2, PfDHFR, PfDXR, and Falcipain-2 is 0.1 to 0.5, 0.8, 0.7, and 0.6 nm, respectively. These findings suggest that C. pareira and its flavonoids hold potential as broad-spectrum antimalarial agents, which could pave the way for further investigation and development of novel therapeutics to combat this deadly disease.