Abstract
The X-ray crystal structures of complexes between the antimalarial drugs quinine, quinidine and halofantrine and their biological target, iron(III) ferriprotoporphyrin IX (FePPIX), have been reported in the literature (de Villiers et al. in ACS Chem Biol 7:666, 2012; J Inorg Biochem 102:1660, 2008) and show that all three drugs utilize their zwitterionic alkoxide forms to coordinate to the iron atom via Fe–O bonds. In this work, density functional theory calculations with implicit solvent corrections have been used to model the energetics of formation of these complexes. It is found that the cost of formation of the active zwitterionic form of each drug is more than offset by the energy of its binding to FePPIX, such that the overall energies for complexation of all three drugs with FePPIX are moderately favourable in water, and rather more favourable in n-octanol as solvent. The calculations have been extended to develop an analogous model for the complex between FePPIX and chloroquine, whose structure is not presently known from experiment.
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Notes
Throughout this paper, FePPIX is used to indicate the generic form of ferriprotoporphyrin IX. Specific neutral and ionized forms of the protoporphyrin IX ligand are denoted as PPIXH2, PPIXH− and PPIX2−.
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Acknowledgments
Thanks are due to Prof. Tim Egan, University of Cape Town, and to Dr. Katherine de Villiers-Chen, Stellenbosch University, for helpful discussions, and to Northumbria University for the provision of computing facilities.
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Dedicated to the memory of Dr. David R. M. Walton, Founding Editor, Transition Metal Chemistry.
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Acharige, A.M.D.S.D., Durrant, M.C. An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations. Transition Met Chem 39, 721–726 (2014). https://doi.org/10.1007/s11243-014-9868-z
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DOI: https://doi.org/10.1007/s11243-014-9868-z