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Mol Divers. 2019 Feb 1. doi: 10.1007/s11030-019-09919-6. [Epub ahead of print]
Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism.
Malbari KD1, Chintakrindi AS1, Ganji LR1, Gohil DJ2, Kothari ST2, Joshi MV3, Kanyalkar MA4.
Author information
Abstract
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.
KEYWORDS:
430-Loop cavity; Alternate binding mechanism; Cytopathic effect inhibition; Molecular modelling; Pandemic H1N1; Scaffolds; Sialic acid displacement
PMID: 30710224 DOI: 10.1007/s11030-019-09919-6
Structure-aided drug development of potential neuraminidase inhibitors against pandemic H1N1 exploring alternate binding mechanism.
Malbari KD1, Chintakrindi AS1, Ganji LR1, Gohil DJ2, Kothari ST2, Joshi MV3, Kanyalkar MA4.
Author information
Abstract
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.
KEYWORDS:
430-Loop cavity; Alternate binding mechanism; Cytopathic effect inhibition; Molecular modelling; Pandemic H1N1; Scaffolds; Sialic acid displacement
PMID: 30710224 DOI: 10.1007/s11030-019-09919-6