Design of multiligand inhibitors for the swine flu H1N1 neuraminidase binding site

Manoj M Narayanan,^1,2 Chandrasekhar B Nair,² Shilpa K Sanjeeva,² PV Subba Rao,² Phani K Pullela,^1,2 Colin J Barrow<sup>1

1</sup>Centre for Chemistry and Biotechnology, Deakin University, Geelong, VIC, Australia; ²Bigtec Pvt Ltd, Rajajinagar, Bangalore, India

Abstract: Viral neuraminidase inhibitors such as oseltamivir and zanamivir prevent early virus multiplication by blocking sialic acid cleavage on host cells. These drugs are effective for the treatment of a variety of influenza subtypes, including swine flu (H1N1). The binding site for these drugs is well established and they were designed based on computational docking studies. We show here that some common natural products have moderate inhibitory activity for H1N1 neuraminidase under docking studies. Significantly, docking studies using AutoDock for biligand and triligand forms of these compounds (camphor, menthol, and methyl salicylate linked via methylene bridges) indicate that they may bind in combination with high affinity to the H1N1 neuraminidase active site. These results also indicate that chemically linked biligands and triligands of these natural products could provide a new class of drug leads for the prevention and treatment of influenza. This study also highlights the need for a multiligand docking algorithm to understand better the mode of action of natural products, wherein multiple active ingredients are present.

Keywords: neuraminidase, influenza, H1N1, multiligand, binding energy, molecular docking, virus