Abstract
Background: Resistance to existing antifolate drugs targeting the dihydrofolate reductase (DHFR) enzyme in Plasmodium falciparum is a major obstacle to malaria control. Furthermore, some current drugs have associated toxicity concerns. To address this, we explored new antifolate inhibitors to develop safer and more potent antimalarial drugs.
Methods: We computationally screened hypothetical compounds A1, A2, and A3 (a parent compound and two alcohol derivatives) for their toxicity and inhibitory effectiveness against the bifunctional DHFR-thymidylate synthase enzyme. Their physicochemical properties, drug-likeness, toxicity, and binding energies were compared to ten standard antimalarial drugs using computational tools like Molinspiration, SwissADME, Protox II, and AutoDock Vina. Density functional theory (DFT) studies were also conducted to understand the electronic properties influencing binding.
Results: All three compounds (A1, A2, and A3) were predicted to be non-toxic and showed favorable drug-like properties, including high gastrointestinal absorption. Compound A1 exhibited a strong binding score of -9.20 kcal/mol, comparable to the drug Artesunate. A2 and A3 also showed potent binding scores of -8.8 kcal/mol and -8.2 kcal/mol, respectively, surpassing Mefloquine. DFT studies revealed a correlation between the binding trend and the compounds’ electron affinity (EA) and electronic chemical potential (μ) values.
Conclusion: The results suggest that our investigated compounds, particularly A1 and A3, are promising, non-toxic candidates for further development as antimalarial drugs.
Keywords: Plasmodium falciparum; dihydrofolate reductase; molecular docking; piperazine derivatives.
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