Background: Development of resistance by the malaria parasite Plasmodium falciparum
has created challenges in the eradication of this deadly infectious disease. Hence newer strategies
are adopted to combat this disease and simultaneously, new lead/hit identification is going
on worldwide to develop new chemotherapeutic agents against malaria.
Objective: In this study, 44 flavonoids found mainly in the fruit juice of Citrus species having traditional
use in malaria-associated fever were selected for in silico multiple-target directed screening
against three vital targets of the parasite namely dihydroorotate dehydrogenase (PfDHODH),
dihydrofolate reductase thymidine synthase (PfDHFR-TS) and plasma membrane P-type cation
translocating ATPase (PfATP4) to find out new lead molecule(s).
Methods: The in silico screening was carried out using different protocols of the Biovia Discovery
Studio 2018 software and Network analyzer plugin of Cytoscape 3.6.0 followed by in vitro screening
of the best lead.
Results: After screening, CF8 or luteolin was found to have good binding affinity against
PfDHODH and PfATP4 with –CDocker energy 42.2719 and 33.1447 with respect to their cocrystal
ligands. These findings were also supported by structure-based pharmacophore, DFT (Density
Functional Theory) study and finally by in vitro screening of the lead with IC50 values of 8.23
μm and 12.41 μm against 3D7 (chloroquine-sensitive) and RKL-9 (chloroquine-resistant) strain of
P. falciparum, respectively.
Conclusion: Our study found a moderately active lead molecule with the predicted mode of action
which can be utilized to design some new derivatives with more safety and efficacy by targeting
the two enzymes.