Evaluation of Au(III) complexes as Plasmodium falciparum aquaglyceroporin (PfAQP) inhibitors by in silico and in vitro methods.

The onset of resistance to artemisinin for malaria treatment has stimulated the quest for novel antimalarial drugs. Herein, the gold(III) coordination complexes Aubipy [Au(bipy)Cl] (bipy = 2,2'-bipyridine), Auphen [Au(phen)Cl] (phen = phenanthroline), Auterpy [Au(terpy)Cl] (terpy = 2,2';6',2″-terpyridine), and corresponding hydrolyzed species, have been investigated as inhibitors of the Plasmodium falciparum aquaglyceroporin (PfAQP) protein by computational methods. Through an in-silico approach using an Umbrella Sampling protocol to sample how Aubipy, Auphen, and Auterpy permeate through the PfAQP, their permeability coefficients were estimated using the Inhomogeneous Solubility Diffusion (ISD) model with promising results. The efficacy of the gold complexes was then probed by an in vitro assay testing the growth inhibition in chloroquine sensitive and resistant P. falciparum strains. In accordance with the computational data, Auterpy achieved the highest efficiency with an IC in the nanomolar range (590 nM) on resistant strain cultures, additionally revealing a good selectivity as compared to its activity against the human aquaglyceroporin 3.