Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors.

Abstract:

BACKGROUND: Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor beta, a folate/antifolate transporter. METHODS: We computationally compared the structural, dynamic and physico-chemical properties of the targets. We based our analysis on available inhibitory activity and crystallographic data, including a crystal structure of the bifunctional T. cruzi DHFR-TS with tetrahydrofolate bound determined in this work. Due to the low sequence and structural similarity of the targets analyzed, we employed a mapping of binding pockets based on the known common ligands, folate and methotrexate. RESULTS: Our analysis provides a set of practical strategies for the design of selective trypanosomatid folate pathway inhibitors, which are supported by enzyme inhibition measurements and crystallographic structures. CONCLUSIONS: The ligand-based comparative computational mapping of protein binding pockets provides a basis for repurposing of anti-folates and the design of new anti-trypanosmatid agents. GENERAL SIGNIFICANCE: Apart from the target-based discovery of selective compounds, our approach may be also applied for protein engineering or analyzing evolutionary relationships in protein families.

SEEK ID: https://fairdomhub.org/publications/563

PubMed ID: 28939533

Projects: NMTrypI - New Medicines for Trypanosomatidic Infections

Publication type: Journal

Journal: Biochim Biophys Acta Gen Subj

Citation: Biochim Biophys Acta Gen Subj. 2017 Dec;1861(12):3215-3230. doi: 10.1016/j.bbagen.2017.09.012. Epub 2017 Sep 20.

Date Published: 25th Sep 2017

Registered Mode: by PubMed ID

Authors: J. Panecka-Hofman, I. Pohner, F. Spyrakis, T. Zeppelin, F. Di Pisa, L. Dello Iacono, A. Bonucci, A. Quotadamo, A. Venturelli, S. Mangani, M. P. Costi, R. C. Wade

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