Molecular investigation of artificial and natural sweeteners as potential anti-inflammatory agents

Abstract

Repurposing existing drugs, as well as natural and artificial sweeteners for novel therapeutic indications could speed up the drug discovery process since numerous associated risks and costs for drug development can be surpassed. In this study, natural and artificial sweeteners have been evaluated by in silico and experimental studies for their potency to inhibit lipoxygenase enzyme, an enzyme participating in the inflammation pathway. A variety of different methods pinpointed that aspartame inhibits the lipoxygenase isoform 1 (LOX-1). In particular, “LOX-aspartame” complex, that was predicted by docking studies, was further evaluated by Molecular Dynamics (MD) simulations in order to assess the stability of the complex. The binding energy of the complex has been calculated after MD simulations using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method. Furthermore, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations have been applied for geometry optimization of the “enzyme-ligand” complex. After having fully characterized the “LOX-aspartame” complex in silico, followed in vitro biological assays confirmed that aspartame inhibits LOX-1 (IC₅₀=50 ± 3.0 μΜ) and blocks its biological response. The atomic details of aspartame’s interaction profile with LOX-1 were revealed through Saturation Transfer Difference (STD) NMR (Nuclear Magnetic Resonance). Finally, aspartame was also tested with Molecular Docking and Molecular Dynamics studies for its potent binding to a number of different LOX isoforms of many organisms, including human. The in silico methods indicated that aspartame could serve as a novel starting point for drug design against LOX enzyme.

Communicated by Ramaswamy H. Sarma

Keywords:

• Aspartame
• lipoxygenase
• molecular dynamics
• STD NMR
• in vitro assays

Acknowledgements

Materials were supported by Special Account for Research Grants (SARG), National Kapodistrian University of Athens (NKUA).

Disclosure statement

The authors declare no conflict of interest.

Author contributions

Conceptualization, T.M. T.T, D.T, I.K and E.C.; methodology, A.K.; software, E.C.; S.K. D.K, I.G; validation, T.M.; E.C; C.D.P; M.V.C, S.K.; writing—original draft preparation, T.M.; E.C; C.D.P; M.V.C writing—review and editing, T.M; A.G.T visualization, A.G., T.M; supervision, M.T.; A.G.T; D.H.-L.

Additional information

Funding

This work was financially supported by Greece and the European Union (European Social Fund- ESF) through the Operational Programme «Human Resources Development, Education and Lifelong Learning» in the context of the project “Strengthening Human Resources Research Potential via Doctorate Research” under Grant MIS-5000432, implemented by the State Scholarships Foundation (ΙΚΥ).