Balgera Federico, Tijani Muyideen Kolapo, Wennerberg Johan, Persson Kristina E M, Nordlander Ebbe, Ferreira Ricardo J
Red Glead Discovery AB, Medicon Village, Scheelevägen 10, 223 63, Lund, Sweden.
Chemical Physics, Department of Chemistry, Lund University, Box 124, 221 00, Lund, Sweden.
J Biol Inorg Chem. 2024 Dec;29(7-8):821-836. doi: 10.1007/s00775-024-02081-x. Epub 2024 Nov 23.
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.
疟疾治疗中对青蒿素耐药性的出现刺激了对新型抗疟药物的探索。在此，通过计算方法研究了金(III)配位络合物Aubipy [Au(bipy)Cl]（bipy = 2,2'-联吡啶）、Auphen [Au(phen)Cl]（phen = 菲咯啉）、Auterpy [Au(terpy)Cl]（terpy = 2,2';6',2″-三联吡啶）以及相应的水解产物作为恶性疟原虫水甘油通道蛋白（PfAQP）的抑制剂。通过使用伞形抽样协议的计算机模拟方法来抽样Aubipy、Auphen 和 Auterpy 如何透过PfAQP，利用非均相溶解度扩散（ISD）模型估计它们的渗透系数，结果很有前景。然后通过体外试验检测金络合物对氯喹敏感和耐药的恶性疟原虫菌株生长抑制的效果来探究其疗效。与计算数据一致，Auterpy在耐药菌株培养物上实现了最高效率，IC在纳摩尔范围内（590 nM），此外，与其对人水甘油通道蛋白3的活性相比，还显示出良好的选择性。
