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The Folate Pathway as Target for Antimalarial Activity: Molecular Docking of Sulfonamides with Plasmodium and Bacterial Dihydropteroate Synthase

Abstract

Malaria caused by Plasmodium falciparum continues to be a major world health scourge. The inhibition of enzymes in the folate pathway critical for synthesis of nucleotides and amino acids plays a role in treatment of malaria. The bifunctional enzyme complex, dihydrofolate reductase thymidylate synthase (DHFR-TS) is a folate pathway enzyme target with numerous amino acid mutations, that may render antimalarial agents ineffective. Herein the effects of DHFR-TS mutations on interactions affinity with antimalarial agents and sulfonamide ligands are explored with using AutoDock 4.2 molecular docking. The affinity of four sulfonamide was compared to artesunate a benchmark antimalarial drug. The effect on binding affinity of fluorine and heterocyclic ring substitution are also explored. The structures of the sulfonamides were optimized with Gaussian at DFT theory using the 6-311+g(d) basis set. All ligands prefer Plasmodium DHFR-TS compared to human DHFR. The heterocyclic sulfonamides show binding energies on same order benchmark drug. The interactions occur with dissociation constants in the micromolar range and stronger affinity than antimalarial drugs; primaquine, pyrimethamine and chloroquine. Polar contacts (GLN541,ASN361), hydrophobic (PHE354) and hydrogen bonding (ASN338, ASN340) interactions are responsible for the strong interactions.

Acknowledgements

GGC Departmet of Science and Technology

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