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In Silico and Whole Cell-based In vitro screening of Flavonoids from Citrus species towards the identification of Antimalarial Lead(s) and Prediction of Mode of Action

Copyright: © 2020  . This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Development of resistance by the malaria parasite Plasmodium falciparum has put challenges in the eradication of deadly malaria disease. Hence, newer strategies are being considered to combat this disease and research programmes with the target of new lead identification are going on worldwide to develop new chemotherapeutic agents. In this study, flavonoids found mainly in the fruits 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, dihydrooroate dehydrogenase (PfDHODH), dihydrofolate reductase thymidine synthase (PfDHFR-TS) and plasma membrane P-type cation translocating ATPase (PfATP4) to find out new lead molecule(s). 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. The selected lead was found to have good binding affinity against PfDHODH and PfATP4 with –CDocker energy 42.2719 and 33.1447 with respect to their co-crystal ligands. These findings were also supported by Structure-based Pharmacophore, DFT (Density Functional Theory) study and also by in vitro evaluation of the lead which showed IC₅₀ value of 8.23 µm and 12.41 µm against 3D7 (chloroquine-sensitive) and RKL-9 (chloroquine-resistant) strain of P. falciparum respectively. This study could identify a moderately active lead molecule with prediction of mode of action. The research outcome can be utilized to design new antimamarial compounds by targeting the two enzymes.