Design, synthesis and computational studies involving Indole-Coumarin hybrids as galectin-1 inhibitors
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 affin...
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Published in | Chemical papers Vol. 75; no. 6; pp. 2791 - 2805 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Cham
Springer International Publishing
01.06.2021
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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 (K
a
) value of 5.4 × 10
5
M
−1
while
7e
was found to have a slightly higher affinity than
6i
with K
a
of 6.6 × 10
5
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 |
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ISSN: | 2585-7290 0366-6352 1336-9075 |
DOI: | 10.1007/s11696-021-01534-w |