Multitarget, Selective Compound Design Yields Picomolar Inhibitors of a Kinetoplastid Pteridine Reductase 1

27 October 2021, Version 3

Abstract

The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective anti-parasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship for multitarget inhibition. The approach yielded compounds showing picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei, whilst retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.

Keywords

Kinetoplastid
Antiparasitic inhibitors
folate pathway enzymes
structure-based drug design
virtual screening
microwave assisted organic synthesis
structure-activity relationships (SARs)
polypharmacology

Supplementary materials

Title
Description
Actions
Title
pteridine-manuscript Supporting Information
Description
Supplemental Figures S1-9, Supplemental Tables S1-12, Supplemental experimental procedures and compound characterization
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Supplementary weblinks

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