First homology model of Plasmodium falciparum glucose-6-phosphate dehydrogenase: Discovery of selective substrate analog-based inhibitors as novel antimalarial agents

Nelson Alencar, Irene Sola, María Linares, Jordi Juárez-Jiménez, Caterina Pont, Antonio Viayna, David Vílchez, Cristina Sampedro, Paloma Abad, Susana Pérez-Benavente, Jerónimo Lameira, José M. Bautista, Diego Muñoz-Torrero, F Javier Luque

Research output: Contribution to journalArticlepeer-review

Abstract

In Plasmodium falciparum the bifunctional enzyme glucose-6-phosphate dehydrogenase‒6-phosphogluconolactonase (PfG6PD‒6PGL) is involved in the catalysis of the first reaction of the pentose phosphate pathway. Since this enzyme has a key role in parasite development, its unique structure represents a potential target for the discovery of antimalarial drugs. Here we describe the first 3D structural model of the G6PD domain of PfG6PD‒6PGL. Compared to the human enzyme (hG6PD), the 3D model has enabled the identification of a key difference in the substrate-binding site, which involves the replacement of Arg365 in hG6PD by Asp750 in PfG6PD. In a prospective validation of the model, this critical change has been exploited to rationally design a novel family of substrate analog-based inhibitors that can display the necessary selectivity towards PfG6PD. A series of glucose derivatives featuring an α-methoxy group at the anomeric position and different side chains at position 6 bearing distinct basic functionalities has been synthesized, and their PfG6PD and hG6PD inhibitory activities and their toxicity against parasite and mammalian cells have been assessed. Several compounds displayed micromolar affinity (Ki up to 23 μM), favorable selectivity (up to > 26-fold), and low cytotoxicity. Phenotypic assays with P. falciparum cultures revealed high micromolar IC50 values, likely as a result of poor internalization of the compounds in the parasite cell. Overall, these results endorse confidence to the 3D model of PfG6PD, paving the way for the use of target-based drug design approaches in antimalarial drug discovery studies around this promising target.

Original languageEnglish
Pages (from-to)108-122
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Volume146
Early online date4 Feb 2018
DOIs
Publication statusE-pub ahead of print - 4 Feb 2018
Externally publishedYes

Keywords

  • Drug design
  • Glucose-6-phosphate dehydrogenase
  • Homology modeling
  • Malaria
  • Plasmodium falciparum
  • Selective inhibitors

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