Investigations on the binding specificity of β-galactoside analogues with human galectin-1 using molecular dynamics simulations

Abstract

Galectin-1 (Gal-1) is the first member of galectin family, which has a carbohydrate recognition domain, specifically binds towards $\beta$-galactoside containing oligosaccharides. Owing its association with carbohydrates, Gal-1 is involved in many biological processes such as cell signaling, adhesion and pathological pathways such as metastasis, apoptosis and increased tumour cell survival. The development of β-galactoside based inhibitors would help to control the Gal-1 expression. In the current study, we carried out molecular dynamics (MD) simulations to examine the structural and dynamic behaviour Gal-1-thiodigalactoside (TDG), Gal-1-lactobionic acid (LBA) and Gal-1-beta-(1→6)-galactobiose (G16G) complexes. The analysis of glycosidic torsional angles revealed that $\beta$-galactoside analogues TDG and LBA have a single binding mode (BM1) whereas G16G has two binding modes (BM1 and BM2) for interacting with Gal-1 protein. We have computed the binding free energies for the complexes Gal-1-TDG, Gal-1-LBA and Gal-1-G16G using MM/PBSA and are −6.45, −6.22 and −3.08 kcal/mol, respectively. This trend agrees well with experiments that the binding of Gal-1 with TDG is stronger than LBA. Further analysis revealed that the interactions due to direct and water-mediated hydrogen bonds play a significant role to the structural stability of the complexes. The result obtained from this study is useful to formulate a set of rules and derive pharmacophore-based features for designing inhibitors against galectin-1.

Communicated by Ramaswamy H. Sarma

Keywords:

• Galectin-1
• $\beta$-galactoside
• molecular dynamics simulations
• MM/PBSA
• molecular docking

Acknowledgements

We thank the Department of Biotechnology and Indian Institute of Technology Madras for computational facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The work is partially supported by the Department of Biotechnology (DBT), New Delhi, Government of India for partial financial support to KV and MMG (Sanction order No.: BT/PR13410/BID/7/536/2015 and BT/PR12267/BID/7/506/2014). NRS thanks Ministry of Human Resource and Development, India and DST-INSPIRE for fellowship (IF170342).