Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway

ABSTRACT

Introduction

Trypanosomatidic parasitic infections in humans and animals caused by Trypanosoma brucei, Trypanosoma cruzi, and Leishmania species pose a significant health and economic burden in developing countries. There are few effective and accessible treatments for these diseases, and the existing therapies suffer from problems, such as parasite resistance and side effects. Structure-based drug design (SBDD) is one of the strategies that has been applied to discover new compounds targeting trypanosomatid-borne diseases.

Areas covered

We review the current literature (mostly over the last 5 years, searched in the PubMed database on 11 November 2021) on the application of structure-based drug design approaches to identify new anti-trypanosomatidic compounds that interfere with a validated target biochemical pathway, the trypanosomatid folate pathway.

Expert opinion

The application of structure-based drug design approaches to perturb the trypanosomatid folate pathway has successfully provided many new inhibitors with good selectivity profiles, most of which are natural products or their derivatives or have scaffolds of known drugs. However, the inhibitory effect against the target protein(s) often does not translate to anti-parasitic activity. Further progress is hampered by our incomplete understanding of parasite biology and biochemistry, which is necessary to complement SBDD in a multiparameter optimization approach to discovering selective anti-parasitic drugs.

KEYWORDS:

• Dihydrofolate reductase
• folate pathway
• molecular docking
• molecular dynamics
• pteridine reductase 1
• structure-based drug design
• trypanosomatids
• virtual screening

Article highlights

• The trypanosomatid folate pathway is a potential target for antiparasitic drugs.

• Many crystal structures have been solved for the key trypanosomatid folate pathway enzymes.

• Structure-based drug design has led to multitarget, selective enzyme inhibitors.

• Multiple factors must be considered to optimize anti-parasite activity.

• Improved modeling techniques and better knowledge of the biology of parasites should enable the discovery of more potent selective antiparasitic agents.

This box summarizes key points contained in the article.

Abbreviations

DHFR – dihydrofolate reductase	=
DHFR-TS – bifunctional dihydrofolate reductase-thymidylate synthase	=
HAT – Human African Trypanosomiasis	=
hDHFR – human dihydrofolate reductase	=
Lb – Leishmania brasiliensis	=
Lm – Leishmania major	=
Lmex – Leishmania mexicana	=
MD – molecular dynamics	=
MMGBSA – Molecular Mechanics/Generalized Born Surface Area method	=
MMPBSA – Molecular Mechanics/Poisson Boltzmann Surface Area method	=
MTX – methotrexate	=
PLIFs – protein-ligand interaction fingerprints	=
PTR1 – pteridine reductase 1	=
QM – quantum mechanics	=
RF – random forest	=
SAR – Structure-Activity Relationships	=
SBDD – structure-based drug design	=
Tb – Trypanosoma brucei	=
Tbb – Trypanosoma brucei brucei	=
Tbr – Trypanosoma brucei rhodesiense	=
Tc – Trypanosoma cruzi	=
TS – thymidylate synthase	=
VS – virtual screening	=

Declaration of interest

R C Wade is a patent holder of the patent ‘Use of pteridine reductase inhibitors for the prevention and / or treatment of parasitic infections’ (https://iris.unimore.it/handle/11380/649260?mode=full). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17460441.2022.2113776

Additional information

Funding

The work of R C Wade, J Panecka-Hofman and I Poehner was supported by the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 603240 (NMTrypI, New Medicines for Trypanosomatidic Infections, https://fp7-nmtrypi.eu/). R C Wade gratefully acknowledges the support of the Klaus Tschira Foundation. J Panecka-Hofman acknowledges support from the Polish National Science Centre (grant no. 2016/21/D/NZ1/02806) and the BIOMS program at the Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University. I Poehner gratefully acknowledges the Jane and Aatos Erkko Foundation for financial support.