Title:Rosmarinic Acid as a Potent Influenza Neuraminidase Inhibitor: <i>In Vitro</i> and <i>In Silico</i> Study
VOLUME: 20 ISSUE: 23
Author(s):Panupong Mahalapbutr, Mattanun Sangkhawasi, Jirayu Kammarabutr, Supakarn Chamni* and Thanyada Rungrotmongkol*
Affiliation:Structural and Computational Biology Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330, Program in Biotechnology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Structural and Computational Biology Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330, Natural Products and Nanoparticles Research Unit (NP2), Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Structural and Computational Biology Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Pathumwan, Bangkok 10330
Keywords:Neuraminidase, Caffeic acid, Rosmarinic acid, Hydroxycinnamate analogues, Molecular docking, Molecular dynamics
simulations.
Abstract:
Background: Neuraminidase (NA), a major glycoprotein found on the surface of the influenza
virus, is an important target for the prophylaxis and treatment of influenza virus infections. Recently,
several plant-derived polyphenols, especially caffeic acid analogs, have been reported to exert
the inhibitory activity against NA.
Objective: Herein, we aimed to investigate the anti-influenza NA activity of caffeic acid and its hydroxycinnamate
analogues, rosmarinic acid and salvianolic acid A, in comparison to a known NA inhibitor,
oseltamivir.
Methods: In vitro MUNANA-based NA inhibitory assay was used to evaluate the inhibitory activity of
the three interested hydroxycinnamic compounds towards the influenza NA enzyme. Subsequently, allatom
molecular dynamics (MD) simulations and binding free energy calculations were employed to elucidate
the structural insights into the protein-ligand complexations.
Results: Rosmarinic acid showed the highest inhibitory activity against NA with the IC50 of 0.40 μM
compared to caffeic acid (IC50 of 0.81 μM) and salvianolic acid A (IC50 of >1 μM). From 100-ns MD
simulations, the binding affinity, hot-spot residues, and H-bond formations of rosmarinic acid/NA complex
were higher than those of caffeic acid/NA model, in which their molecular complexations was
driven mainly by electrostatic attractions and H-bond formations from several charged residues (R118,
E119, D151, R152, E227, E277, and R371). Notably, the two hydroxyl groups on both phenyl and
phenylacetic rings of rosmarinic acid play a crucial role in stabilizing NA through a strongly formed Hbond(
s).
Conclusion: Our findings shed light on the potentiality of rosmarinic acid as a lead compound for further
development of a potential influenza NA inhibitor.
