Structure-Based Design of Pteridine Reductase Inhibitors Targeting African Sleeping Sickness and the Leishmaniases

Abstract

Pteridine reductase (PTR1) is a target for drug development against Trypanosoma and Leishmania species, parasites that cause serious tropical diseases and for which therapies are inadequate. We adopted a structure-based approach to the design of novel PTR1 inhibitors based on three molecular scaffolds. A series of compounds, most newly synthesized, were identified as inhibitors with PTR1-species specific properties explained by structural differences between the T. brucei and L. major enzymes. The most potent inhibitors target T. brucei PTR1, and two compounds displayed antiparasite activity against the bloodstream form of the parasite. PTR1 contributes to antifolate drug resistance by providing a molecular bypass of dihydrofolate reductase (DHFR) inhibition. Therefore, combining PTR1 and DHFR inhibitors might improve therapeutic efficacy. We tested two new compounds with known DHFR inhibitors. A synergistic effect was observed for one particular combination highlighting the potential of such an approach for treatment of African sleeping sickness.

3D-QSAR based pharmacophore modeling and virtual screening for identification of novel pteridine reductase inhibitors

“…The diverse inhibitor molecules of PTR1 from L. major reported in literature with experimentally determined K i values were selected for 3D-QSAR studies [11][12][13][14][15][16]. The inhibitor molecules were divided into training and test set so as to cover varied range of the binding affinities and structural diversity.…”

“…R/R 1 and R 2 are the side chains of the scaffolds. The molecules selected as test set with their respective K i values are shown in bold [11][12][13][14][15][16] Recently, various rational structural techniques like structure-based drug design have been used to identify inhibitors against this enzyme [11][12][13][14][15][16][17][18]. This further necessitates exploration of the binding preferences of the known inhibitors in the context of structure activity relationship and the identification of potential novel lead molecules against PTR1.…”

Design, Synthesis and Biological Evaluation of Novel Inhibitors of Trypanosoma brucei Pteridine Reductase 1

“…10, 11 Whilst these templates have a very strong binding interaction with the enzyme, they also have a high polar surface area (PSA), which may cause problems with blood–brain barrier (BBB) permeability and is associated with solubility problems. In addition, most of the known PTR1 inhibitors are not particularly selective and could also inhibit human DHFR, causing toxicity issues 10, 12. Therefore, we recently reported the virtual screening of a fragment library to identify new scaffolds with a lower PSA 13.…”

Structure-Based Design and Synthesis of Antiparasitic Pyrrolopyrimidines Targeting Pteridine Reductase 1

“…7 Two possible binding poses are observed. One orientation is termed the substrate-like pose and corresponds to how substrates such as oxidized pterins and pteridines bind.…”