Validation of ligands targeting metacaspase-2 (MCA2) from Trypanosoma brucei brucei and their application to MCA5 from T. congolense as possible trypanocides.

Autor: Eyssen LE; Biochemistry, School of Life Sciences, University of KwaZulu-Natal (Pietermaritzburg Campus), Private Bag X01, Scottsville, 3209, South Africa., Coetzer TH; Biochemistry, School of Life Sciences, University of KwaZulu-Natal (Pietermaritzburg Campus), Private Bag X01, Scottsville, 3209, South Africa. Electronic address: coetzer@ukzn.ac.za.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2020 Jun; Vol. 97, pp. 107579. Date of Electronic Publication: 2020 Mar 06.
DOI: 10.1016/j.jmgm.2020.107579
Abstrakt: Metacaspases (MCAs) are ideal drug and diagnostic targets for animal and human African trypanosomiasis, as these cysteine peptidases are absent from the metazoan kingdom and have been implicated in the parasite cell cycle and cell death. Tsetse fly-transmitted trypanosomes that live free in the bloodstream and/or cerebrospinal fluid of the mammalian host cause animal and human African trypanosomiasis (nagana or sleeping sickness respectively). Chemotherapy and chemoprophylaxis are the main forms of control, but in contrast to human trypanocides, the veterinary drugs are old and drug resistance is on the increase. A peptidomimetic library targeting the MCA2 from Trypanosoma brucei brucei has ligands with low IC 50 values, some of which were antiparasitic. This study validates the inhibitory activity of these ligands using the protein structure solved by X-ray diffraction after the ligand library was published. Water molecules were shown to be important in substrate binding and strategies to improve the efficacy of these ligands are highlighted. These ligands appear to be pan-specific as they were docked into the active site of the homology modelled MCA5 of animal infective Trypanosoma congolense with similar binding energies and conformations.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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