Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays

Kimuda, Magambo Phillip; Laming, Dustin; Hoppe, Heinrich C; Tastan Bishop, Özlem

Title: Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays
Creator: Kimuda, Magambo Phillip
Creator: Laming, Dustin
Creator: Hoppe, Heinrich C
Creator: Tastan Bishop, Özlem
Date Issued: 2019
Date: 2019
Type: text
Type: article
Identifier: http://hdl.handle.net/10962/124675
Identifier: vital:35647
Identifier: https://doi:10.3390/molecules24010142
Description: Pteridine reductase 1 (PTR1) is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of Trypanosoma brucei dihydrofolate reductase (TbDHFR) and Trypanosoma brucei pteridine reductase 1 (TbPTR1) has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to molecular dynamics to characterize their molecular interactions and energetics, followed by in vitro testing. In this study, we identified five compounds which showed low micromolar Trypanosome growth inhibition in in vitro experiments that might be acting by inhibition of TbPTR1. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism (mutual reduction in potency) when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Overall, our results provide a basis for scaffold optimization for further studies in the development of HAT anti-folates.
Format: 25 pages
Format: pdf
Language: English
Relation: Molecules
Relation: Kimuda, M., Laming, D., Hoppe, H. and Tastan Bishop, Ö., 2019. Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays. Molecules, 24(1), p.142
Relation: Molecules volume 24 number 142 1 25 2019 1420-3049
Rights: Molecules
Rights: Use of this resource is governed by the terms and conditions of the MDPI Open Access Policy statement (https://www.mdpi.com/about/openaccess)

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Tastan Bishop, Ozlem (Prof)

RU Research Unit in Bioinformatics (RUBi)

RU Department of Biochemistry, Microbiology and Biotechnology

RU Centre for Chemico- and Biomedicinal Research (CCBR)

Hoppe, Heinrich C (Prof)

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