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

DOI: 10.1016/j.bbagen.2017.09.012 DOI Help

Authors: Joanna Panecka-hofman (Heidelberg Institute for Theoretical Studies (HITS); Centre of New Technologies (CeNT), University of Warsaw) , Ina Pöhner (Heidelberg Institute for Theoretical Studies (HITS)) , Francesca Spyrakis (University of Turin; University of Modena and Reggio Emilia) , Talia Zeppelin (Heidelberg Institute for Theoretical Studies (HITS)) , Flavio Di Pisa (University of Siena) , Lucia Dello Iacono (University of Siena) , Alessio Bonucci (University of Siena) , Antonio Quotadamo (Tydock Pharma srl) , Alberto Venturelli (Tydock Pharma srl) , Stefano Mangani (University of Siena) , Maria Paola Costi (University of Modena and Reggio Emilia) , Rebecca C. Wade (Heidelberg Institute for Theoretical Studies (HITS); Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimica Et Biophysica Acta (bba) - General Subjects

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 11690

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 β, 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.

Journal Keywords: folate pathway; trypanosomatids; structure-based drug design; selective inhibition; enzyme inhibitor; anti-parasitic drug

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography