Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors

Abstract

Human galectins are promising targets for cancer immunotherapeutic and fibrotic disease-related drugs. We report herein the binding interactions of three thio-digalactosides (TDGs) including TDG itself, TD139 (3,3’-deoxy-3,3’-bis-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside, recently approved for the treatment of idiopathic pulmonary fibrosis), and TAZTDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside) with human galectins-1, -3 and -7 as assessed by X-ray crystallography, isothermal titration calorimetry and NMR spectroscopy. Five binding subsites (A–E) make up the carbohydrate-recognition domains of these galectins. We identified novel interactions between an arginine within subsite E of the galectins and an arene group in the ligands. In addition to the interactions contributed by the galactosyl sugar residues bound at subsites C and D, the fluorophenyl group of TAZTDG preferentially bound to subsite B in galectin-3, whereas the same group favored binding at subsite E in galectins-1 and -7. The characterised dual binding modes demonstrate how binding potency, reported as decreased Kd values of the TDG inhibitors from μM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.

Molecular Docking and Binding Free Energy Analysis of Rutin and Apigetrin as Galectin-1 Inhibitors

“…Another experiment, involved interactions between galetin-1 protein with thiodigalactoside derivative, TDG139, where interactions were made by Ser29, Val31, Asp54, Arg73, Glu71, Arg48 and Asn46 residues [59]. Ligands of this experiment made common interactions by Ser29, Val31, Arg48 and Glu71 residues, which were also supported by previous…”

Galectin-3 Is a Potential Mediator for Atherosclerosis

“…Thiodigalactoside (TDG) derivatives targeting CRD sites have been approved as antagonists of Gal-3. TD-139, a thiodigalactoside analogue, has been used as an inhaled powder for the treatment of idiopathic pulmonary fibrosis and is speculated to antagonize Gal-3 [92]. Multivalent attachment of a TDG derivative using the bovine serum albumin has been identified as one of the most potent Gal-3 inhibitors so far [93].…”

Multivalent Lactose–Ferrocene Conjugates Based on Poly (Amido Amine) Dendrimers and Gold Nanoparticles as Electrochemical Probes for Sensing Galectin-3

“…However, while Fc-Lac dendrimers 12 and 13 showed n values below and relatively close to the theoretically expected values for a tetramer (1/2 = 0.25) and an octamer (1/8 = 0.125), Fc-Lac 16-mer 14 showed a value larger than that theoretically expected (1/16 = 0.063), which indicates that, for this compound, not all of the lactoside residues participate in the binding, as noted above. It is noteworthy to mention that the binding affinity of Fc-Lac dendrimers, and particularly hexadecamer 14, is within the range of magnitude of the potent Gal-3 inhibitors [4,60]. Therefore, they can be applied as anti-Gal-3 agent for therapeutic purposes.…”