Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors

Abstract

In continuation of our quest to develop non-carbohydrate galectin-1 inhibitors, we have designed and synthesized 20 indole-coumarin hybrids linked via chalcone. Compounds 6i and 7e were found to decrease galectin-1 levels significantly in galectin-1 enzyme assay at 20 µM concentration. Binding affinity studies carried out by fluorescence spectroscopy revealed that 6i binds to galectin-1 with a binding constant (Ka) value of 5.4 × 105 M−1 while 7e was found to have a slightly higher affinity than 6i with Ka of 6.6 × 105 M−1. Molecular docking was carried out to ascertain the interaction between ligand and protein. To further gain structural insights into the binding of the compounds, 30 ns molecular dynamic simulations were carried out. The studies revealed that compound 7e was stable within the subsite C of galectin carbohydrate recognition domain while 6i fluctuated throughout the simulation. In addition, 7e maintained continuous interaction with Trp68 and His52, the two key amino acid residues are responsible for recognition of ligands within the active site. Furthermore, 7e displayed H-bond interactions with highly conserved amino acids within galectin-1 CRD, i.e., Arg48, Asn61 and Glu71. Free energy of binding evaluated by MM-GBSA calculations was also in accordance with experimental data. 7e was calculated to have binding energy of − 53.40 kcal/mole while 6i was found to have a value of − 45.63 kcal/mole. Graphical abstract: [Figure not available: see fulltext.]