An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

Acharige, Anjana and Durrant, Marcus (2014) An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations. Transition Metal Chemistry, 39 (7). pp. 721-726. ISSN 0340-4285

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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.

Item Type: Article
Additional Information: Published online August 2014 ahead of print
Subjects: C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Nicola King
Date Deposited: 28 Aug 2014 12:27
Last Modified: 25 Oct 2017 02:55

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