RT Journal Article
T1 First homology model of Plasmodium falciparum glucose-6-phosphate dehydrogenase: Discovery of selective substrate analog-based inhibitors as novel antimalarial agents
A1 Alencar, Nelson
A1 Sola, Irene
A1 Linares Gómez, María
A1 Juárez-Jiménez, Jordi
A1 Pont, Caterina
A1 Viayna, Antonio
A1 Vílchez, David
A1 Sampedro, Cristina
A1 Abad, Paloma
A1 Pérez-Benavente, Susana
A1 Lameira, Jerónimo
A1 Bautista Santa Cruz, José Manuel
A1 Muñoz-Torrero, Diego
A1 Luque, F. Javier
AB 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.
PB Elsevier
SN 0223-5234
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/93568
UL https://hdl.handle.net/20.500.14352/93568
LA eng
NO Alencar N, Sola I, Linares M, Juárez-Jiménez J, Pont C, Viayna A, et al. First homology model of Plasmodium falciparum glucose-6-phosphate dehydrogenase: Discovery of selective substrate analog-based inhibitors as novel antimalarial agents. European Journal of Medicinal Chemistry 2018;146:108–22. https://doi.org/10.1016/j.ejmech.2018.01.044.
NO Ministerio de Economía y Competitividad (España)
NO Universidad of Barcelona
NO Comunidad de Madrid
DS Docta Complutense
RD 5 abr 2025