ArticleMolecules (Basel, Switzerland)2016
Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi.
Article in Molecules (Basel, Switzerland), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 20 citations in OpenAlex.
- Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2022Article
- Biochemical and Kinetic Characterization of the Glucose-6-Phosphate Dehydrogenase fromMicroorganisms · 2022Article
- Boosting the Discovery of Small Molecule Inhibitors of Glucose-6-Phosphate Dehydrogenase for the Treatment of Cancer, Infectious Diseases, and Inflammation.Journal of medicinal chemistry · 2022Review
- Glucose 6-Phosphate Dehydrogenase from Trypanosomes: Selectivity for Steroids and Chemical Validation in BloodstreamMolecules (Basel, Switzerland) · 2021Article
- Characterizing the Fused TvG6PD::6PGL Protein from the ProtozoanInternational journal of molecular sciences · 2020Article
- Development of Selective Steroid Inhibitors for the Glucose-6-phosphate Dehydrogenase fromACS medicinal chemistry letters · 2020Article
- Appraisal of anti-protozoan activity of nitroaromatic benzenesulfonamides inhibiting carbonic anhydrases fromJournal of enzyme inhibition and medicinal chemistry · 2019Article
- Molecular Cloning and Exploration of the Biochemical and Functional Analysis of Recombinant Glucose-6-Phosphate Dehydrogenase fromInternational journal of molecular sciences · 2019Article
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6 authors at 4 institutions in 4 countries.
Funding
Abstract
Glucose-6-phosphate dehydrogenase (G6PDH) plays a housekeeping role in cell metabolism by generating reducing power (NADPH) and fueling the production of nucleotide precursors (ribose-5-phosphate). Based on its indispensability for pathogenic parasites from the genus Trypanosoma, G6PDH is considered a drug target candidate. Several steroid-like scaffolds were previously reported to target the activity of G6PDH. Epiandrosterone (EA) is an uncompetitive inhibitor of trypanosomal G6PDH for which its binding site to the enzyme remains unknown. Molecular simulation studies with the structure of Trypanosoma cruzi G6PDH revealed that EA binds in a pocket close to the G6P binding-site and protrudes into the active site blocking the interaction between substrates and hence catalysis. Site directed mutagenesis revealed the important steroid-stabilizing effect of residues (L80, K83 and K84) located on helix α-1 of T. cruzi G6PDH. The higher affinity and potency of 16α-Br EA by T. cruzi G6PDH is explained by the formation of a halogen bond with the hydrogen from the terminal amide of the NADP+-nicotinamide. At variance with the human enzyme, the inclusion of a 21-hydroxypregnane-20-one moiety to a 3β-substituted steroid is detrimental for T. cruzi G6PDH inhibition. The species-specificity of certain steroid derivatives towards the parasite G6PDH and the corresponding biochemically validated binding models disclosed in this work may prove valuable for the development of selective inhibitors against the pathogen's enzyme.
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