Molecular insights into trypanothione reductase‐inhibitor interaction: A structure‐based review

Abstract

Information on how small molecules bind to the target enzyme has the potential to impact immensely on how medicinal chemists go about antiparasitic drug discovery. In this review, for the first time, we intend to make an assessment of the structural aspects of trypanothione reductase as drug target, and its complexes with several reversible drugs from the Protein Data Bank (PDB). We attempt to reveal the mechanism of these interactions by careful accounting of the X-ray structures and their possible roles in biological activity to treat Trypanosomatidae diseases. We focus on some of the outstanding findings from structures that are relevant to anti-trypanocidal drug discovery. We also review new interesting compounds that have appeared in the literature based on these X-ray structures.

5-Vinylquinoline-substituted nitrofurans as inhibitors of trypanothione reductase and antitrypanosomal agents

“…For this reason, we further address the properties of trypanothione reductase. According to the crystallographic data of TR complexes with numerous aromatic and heteroaromatic compounds, they bind closely to the TS 2 -binding site, and most frequently act as noncompetitive to TS 2 inhibitors ( [13], and references therein). The amino acid residues involved in their binding, Ser-14, Leu-17, Glu-18, Trp-21, Asn-22, Ser-109, Tyr-110, Met-113 and Phe-114, are conserved in TR of T. congolense, T. cruzi and T. brucei [23].…”

“…T(SH) 2 is the major low molecular weight antioxidant that is synthesized by trypanothione synthase [11]. Because of the absence of catalase and glutathione-dependent enzymes, the antioxidant system in trypanosomes relies mainly on TS 2 -dependent enzymes [12,13]. Thus, the inhibition of TR may weaken the parasite antioxidant system and disturb its redox metabolism and signal transduction [13].…”

“…Because of the absence of catalase and glutathione-dependent enzymes, the antioxidant system in trypanosomes relies mainly on TS 2 -dependent enzymes [12,13]. Thus, the inhibition of TR may weaken the parasite antioxidant system and disturb its redox metabolism and signal transduction [13]. TR is a dimer containing FAD and catalytic disulfide in the 52 kD subunit.…”

“…The structure of TR is similar to that of human erythrocyte glutathione reductase (HGR) except the negative charge in the TS 2 -binding site [13,14]. It is assumed that nitrofurans, like other aromatic TR inhibitors, may bind close to this site ( [13,14], and references therein). In addition, nitrofurans may be slowly reduced by TR in a single-electron way with subsequent redox cycling [4,8].…”

Recent Advancement in the Search of Innovative Antiprotozoal Agents Targeting Trypanothione Metabolism

“…These features, in turn, reflect steric and electrostatic differences between respective active sites, which are importantly affected by the replacement of five residues of GR (Ala34, Arg37, Ile113, Asn117 and Arg347) by Glu18, Trp21, Ser109, Met113 and Ala343 in TR ( L. infantum numbering). In particular, the first four residues constitute a hydrophobic cleft within TR active site in which Glu18 introduces a net negative charge promoting binding of the positively charged substrate [9,11,19–21] …”