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Abstract
BackgroundNeuraminidase (NA) is a prominent surface antigen of Influenza viruses, which helps in release of viruses from the host cells after replication. Anti influenza drugs such as Oseltamivir target a highly conserved active site of NA, which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) to restrict viral release from host cells, thus inhibiting its ability to cleave sialic acid residues on the cell membrane. Reports on the emergence of Oseltamivir resistant strains of H1N1 Influenza virus necessitated a search for alternative drug candidates. Pleconaril is a novel antiviral drug being developed by Schering-Plough to treat Picornaviridae infections, and is in its late clinical trials stage. Since, Pleconaril was designed to bind the highly conserved hydrophobic binding site on VP1 protein of Picorna viruses, the ability of Pleconaril and its novel substituted derivatives to bind highly conserved hydrophobic active site of H1N1 Neuraminidase, targeting which oseltamivir has been designed was investigated.Result310 novel substituted variants of Pleconaril were designed using Chemsketch software and docked into the highly conserved active site of NA using arguslab software. 198 out of 310 Pleconaril variants analyzed for docking with NA active site were proven effective, based on their free binding energy.ConclusionPleconaril variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.
Highlights
Neuraminidase (NA) is a prominent surface antigen of Influenza viruses, which helps in release of viruses from the host cells after replication
All the 310 variants of Pleconaril molecule were analyzed for binding with the active site of NA. 198 out of these were found to have optimum binding efficiency, based on the binding energy calculations in comparison with Oseltamivir
Further investigations showed that Oseltamivir formed 6 hydrogen bonds with TYR 406, GLU 277, ARG 224 (Figure 4) and Pleconaril formed 6 hydrogen bonds with SER 246, PRO 245, ARG 118 amino acid residues (Figure 5), whereas the best Pleconaril variant formed 9 hydrogen bonds with ARG 118, ASN 347, ARG 371 and GLU 277 amino acid residues of NA active site
Summary
Neuraminidase (NA) is a prominent surface antigen of Influenza viruses, which helps in release of viruses from the host cells after replication. Anti influenza drugs such as Oseltamivir target a highly conserved active site of NA, which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) to restrict viral release from host cells, inhibiting its ability to cleave sialic acid residues on the cell membrane. Most of the early antiviral drugs were discovered after screening large number of possible drug compounds using trial and error method This approach has been largely replaced by rational drug design, in which, a target viral protein is identified for the drug [1].
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