Unveiling the structural and retrosynthetic mechanism of some 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate compounds as treatment of malaria parasite, Plasmodium falciparum: MD simulation, binding free energy calcul

Computer-aided drug screening by molecular docking, molecular dynamics (MD), ADMET, and free energy approaches can offer an efficient approach to identify promising drug candidates for malaria treatment. In this study, computational screening was performed by molecular docking of some selected approved drugs and 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate compounds against the malaria parasite, Plasmodium falciparum . Based on previously reported potential therapeutic uses of Plasmodium falciparum compounds, and keeping in mind the dire need of time for the development of potent antimalaria, a combined docking, ADMET properties calculation, molecular dynamics, and free energy approaches were applied in the current study to check the therapeutic potentials of some selected 2-aziridinyl- and 2,3-bis(aziridinyl)-1,4-naphthoquinonyl sulfonate and acylate chief constituents against malaria. Among the studied compounds, we found that CID 14,460,443 (cpd17) and CID 14,460,441 (cpd18), with binding affinities of -11.50 and -11.30 kcal/mol, respectively, compared to the positive controls, have the high potential of binding at malaria enzyme interface and thus could be predicted as a plausible inhibitor to disrupt Plasmodium falciparum host interactions. Molecular dynamics simulation of 200 ns well complemented the binding affinity of the compound and revealed strong stability of cpd17 and cpd18 at the docked site. Additionally, the free binding energy also affirms the docking results. Compounds cpd17 and cpd18 of the present study, if validated in wet lab experiments, could be used to treat Plasmodium falciparum and could serve as a lead in the future for the development of more effective natural antimalarials against Plasmodium falciparum .