Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism
The rate of mutability of pathogenic H1N1 influenza virus is a threat. The emergence of drug resistance to the current competitive inhibitors of neuraminidase, such as oseltamivir and zanamivir, attributes to a need for an alternative approach. The design and synthesis of new analogues with alternate approach are particularly important to identify the potential neuraminidase inhibitors which may not only have better anti-influenza activity but also can withstand challenge of resistance. Five series of scaffolds, namely aurones (1a–1e), pyrimidine analogues (2a–2b), cinnamic acid analogues (3a–3k), chalcones (4a–4h) and cinnamic acid linkages (5a–5c), were designed based on virtual screening against pandemic H1N1 virus. Molecular modelling studies revealed that the designed analogues occupied 430-loop cavity of neuraminidase. Docking of sialic acid in the active site preoccupied with the docked analogues, i.e. in 430-loop cavity, resulted in displacement of sialic acid from its native pose in the catalytic cavity. The favourable analogues were synthesized and evaluated for the cytotoxicity and cytopathic effect inhibition by pandemic H1N1 virus. All the designed analogues resulting in displacement of sialic acid suggested alternate binding mechanism. Overall results indicated that aurones can be measured best among all as potential neuraminidase inhibitor against pandemic H1N1 virus.
KeywordsPandemic H1N1 Scaffolds Molecular modelling 430-Loop cavity Sialic acid displacement Cytopathic effect inhibition Alternate binding mechanism
Foetal bovine serum
Madin-Darby canine kidney cells
Minimum essential medium
National Centre for Disease Control
World Health Organization
M. A. Kanyalkar thanks Indian Council of Medical Research (ICMR), New Delhi, for funding computational facilities at Prin. K. M. Kundnani College of Pharmacy through Adhoc research scheme (58/36/2013-BMS). K. D. Malbari thanks ICMR, New Delhi, for Senior Research Fellowship (58/36/2013-BMS). A. S. Chintakrindi also thanks ICMR, New Delhi, for Senior Research Fellowship (58/27/2007-BMS). K. D. Malbari, D. J. Gohil and S. T. Kothari acknowledge National Centre for Disease Control (NCDC), New Delhi, for providing Madin-Darby canine kidney (MDCK) cell line and thank Haffkine Institute for providing Pandemic Influenza A (H1N1) Mumbai Isolate for cytopathic effect inhibition assay. M. V. Joshi acknowledges National NMR Facility provided by TIFR, Colaba.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
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