Targeting a Large Active Site: Structure-Based Design of Nanomolar Inhibitors of Trypanosoma brucei Trypanothione Reductase.

Abstract

Trypanothione reductase (TR) plays a key role in the unique redox metabolism of trypanosomatids, the causative agents of human African trypanosomiasis (HAT), Chagas' disease, and leishmaniases. Introduction of a new, lean propargylic vector to a known class of TR inhibitors resulted in the strongest reported competitive inhibitor of Trypanosoma (T.) brucei TR, with an inhibition constant Ki of 73 nm, which is fully selective against human glutathione reductase (hGR). The best ligands exhibited in vitro IC50 values (half-maximal inhibitory concentration) against the HAT pathogen, T. brucei rhodesiense, in the mid-nanomolar range, reaching down to 50 nm. X-Ray co-crystal structures confirmed the binding mode of the ligands and revealed the presence of a HEPES buffer molecule in the large active site. Extension of the propargylic vector, guided by structure-based design, to replace the HEPES buffer molecule should give inhibitors with low nanomolar Ki and IC50 values for in vivo studies.

• Authors: Raoul De Gasparo, Ondrej Halgas, Dora Harangozo, Marcel Kaiser, Emil F Pai, R Luise Krauth-Siegel, François Diederich
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 25 Issue 49 Pg. 11416-11421 (Sep 02 2019) ISSN: 1521-3765 [Electronic] Germany
• PMID: 31407832 (Publication Type: Journal Article)
• Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Enzyme Inhibitors
• Ligands
• Protozoan Proteins
• NADH, NADPH Oxidoreductases
• trypanothione reductase

Topics

• Binding Sites
• Catalytic Domain
• Crystallography, X-Ray
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, metabolism)
• Inhibitory Concentration 50
• Ligands
• Molecular Dynamics Simulation
• NADH, NADPH Oxidoreductases (antagonists & inhibitors, metabolism)
• Protozoan Proteins (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Trypanosoma brucei brucei (enzymology)