Structure-Based Design, Docking, and Pharmacophore Mapping of Quinoline Derivatives as Potent Inhibitors of Plasmodium falciparum DHFR: A Computational Antimalarial Study
Keywords:
Quinoline derivatives, Quinoline derivatives, Plasmodium falciparum, Plasmodium falciparum, DHFR inhibition, DHFR inhibition, molecular docking, molecular docking, pharmacophore mapping, pharmacophore mapping, antimalarial drug design, antimalarial drug design, ADMET, ADMETAbstract
Background:Malaria, caused predominantly by Plasmodium falciparum, remains a major global health burden, with rising resistance to existing drugs such as pyrimethamine posing a significant challenge (World Health Organization [WHO], 2023). P. falciparum dihydrofolate reductase (PfDHFR) is a validated target for antimalarial therapy, but resistance mutations necessitate novel inhibitor designs. Quinoline derivatives offer a versatile scaffold with proven antimalarial potential and tunable chemical properties.
Objective:To design, dock, and perform pharmacophore mapping of novel quinoline derivatives against PfDHFR, assessing their binding affinities, key molecular interactions, and predicted pharmacokinetic profiles to identify promising candidates for further development.
Methods:Five quinoline derivatives—QD-1 (4-amino-7-chloroquinoline), QD-2 (2,6-dimethylquinoline), QD-3 (6-methoxyquinoline), QD-4 (quinoline-2-thiol), and QD-5 (quinoline-3-carboxylic acid)—were designed and optimized using density functional theory (DFT) calculations. Molecular docking was performed against PfDHFR (PDB ID: 1J3I) using AutoDock Vina, and 3D binding poses were visualized. ADMET properties were predicted via SwissADME, and pharmacophore mapping was conducted using Phase (Schrödinger).
Results:QD-3 displayed the highest binding affinity (−10.2 kcal/mol), forming stable hydrogen bonds with key residues Ile14, Asp54, and Phe58, alongside strong hydrophobic contacts. QD-1 also demonstrated excellent binding (−9.8 kcal/mol) with favorable ADMET properties. Radar plots indicated that all derivatives were within optimal ranges for oral bioavailability. Pharmacophore mapping revealed that QD-3 and QD-1 matched all critical hydrogen bond donor, acceptor, and aromatic hydrophobic features of the generated model.
Conclusion:Quinoline derivatives, particularly QD-3 and QD-1, exhibit strong PfDHFR inhibitory potential with favorable pharmacokinetic profiles, offering promising scaffolds for next-generation antimalarial development. These in-silico results warrant further in-vitro and in-vivo validation
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Belete, T. M. (2020). Recent progress in the development of new antimalarial drugs with novel targets. Drug Design, Development and Therapy, 14, 3875–3889. https://doi.org/10.2147/DDDT.S253397
Cowman, A. F., Healer, J., Marapana, D., & Marsh, K. (2016). Malaria: Biology and disease. Cell, 167(3), 610–624. https://doi.org/10.1016/j.cell.2016.07.055
Gregson, A., & Plowe, C. V. (2005). Mechanisms of resistance of malaria parasites to antifolates. Pharmacological Reviews, 57(1), 117–145. https://doi.org/10.1124/pr.57.1.4
Nzila, A., Mberu, E. K., Sulo, J., Dayo, H., Winstanley, P., & Watkins, W. M. (2005). Towards an understanding of the mechanism of pyrimethamine-sulfadoxine resistance in Plasmodium falciparum: Genetic and molecular basis. Drug Resistance Updates, 8(4), 183–187. https://doi.org/10.1016/j.drup.2005.03.001
World Health Organization. (2023). World Malaria Report 2023. https://www.who.int/publications/i/item/9789240078444
Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan, S., Vanichtanankul, J., Sirawaraporn, W., Taylor, P., Walkinshaw, M. D., & Yuthavong, Y. (2003). Insights into antifolate resistance from malarial DHFR-TS structures. Nature Structural Biology, 10(5), 357–365. https://doi.org/10.1038/nsb918.
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