Synthesis, molecular docking and dynamics study of novel epoxide derivatives of 1,2,4-trioxanes as antimalarial agents

Malaria infection continues to pose a substantial threat to human health in the twenty-first century. The parasites' resistance against conventional antimalarial drugs creates an emerging demand to develop new and efficient therapeutics against this mosquito-borne infection. Artemisinin, a sesquiterpene lactone, is a potent antimalarial drug found in nature. However, the lack of desirable physicochemical properties actuates researchers to develop new therapeutics based upon this compound. The 1,2,4-trioxane ring system of this natural product was identified as a crucial moiety for exhibiting antimalarial property. A related scientific investigation demonstrates that 1,2,4-trioxane derivatives bind to Plasmodium falciparum dihydrofolate reductase enzymes. The present work reports the synthesis of novel epoxide derivatives of 1,2,4-trioxanes and assesses their receptor binding profile towards Pf-DHFR employing molecular docking and dynamics experiments. The epoxides of 1,2,4-trioxane were synthesized using m-chloroperbenzoic acid and characterized by H-1 & C-13 NMR spectroscopy and mass spectrometry methods. The Pf-DHFR binding profile of epoxide derivatives of 1,2,4-trioxanes was evaluated utilizing in silico methods like Swiss ADME software. Various parameters calculated from 100 ns atomistic molecular dynamics trajectory, including MM-GBSA binding energy calculation, depict a good binding profile of synthesized compounds against this protein.

Automated summary

This study reports the evaluation of the binding profile of epoxide derivatives of 1,2,4-trioxanes to the Pf-DHFR receptor using molecular docking and dynamics experiments. The synthesized compounds showed a good binding profile to the protein.