Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 12 November 2018 / Approved: 14 November 2018 / Online: 14 November 2018 (10:39:01 CET)

A peer-reviewed article of this Preprint also exists.

Kimuda, M.P.; Laming, D.; Hoppe, H.C.; Tastan Bishop, Ö. Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays. Molecules 2019, 24, 142. Kimuda, M.P.; Laming, D.; Hoppe, H.C.; Tastan Bishop, Ö. Identification of Novel Potential Inhibitors of Pteridine Reductase 1 in Trypanosoma brucei via Computational Structure-Based Approaches and in Vitro Inhibition Assays. Molecules 2019, 24, 142.

Journal reference: Molecules 2019, 24, 142
DOI: 10.3390/molecules24010142

Abstract

Pteridine reductase 1 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 TbDHFR and 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 potential TbPTR1 inhibitors that showed low micromolar Trypanosome growth inhibition in in vitro experiments with no significant human cell cytotoxicity. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism 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. Our results provide a basis for scaffold optimization for further studies in the development of HAT antifolates.

Subject Areas

human African trypanosomiasis; pteridine reductase 1; PTR1; DHFR; antifolates; anti-trypanosomal agents; molecular dynamics; dynamic residue network analysis; binding free energy; isobologram assay

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