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In-Silico screening of Pleconaril and its novel substituted derivatives with Neuraminidase of H1N1 Influenza strain.

Hussain Basha S, Prasad RN - BMC Res Notes (2012)

Bottom Line: 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 variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept. of Biotechnology, REVA Institute of Science and Management, Yelahanka, Bangalore 560064, India. hassainbasha53@gmail.com

ABSTRACT

Background: 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, 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.

Result: 310 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.

Conclusion: Pleconaril variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.

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Structure and properties of Oseltamivir.
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Figure 1: Structure and properties of Oseltamivir.

Mentions: Most of the early antiviral drugs were discovered after screening large number of possible drug compounds using trial and error method. Lately, this approach has been largely replaced by rational drug design, in which, a target viral protein is identified for the drug [1]. A detailed picture of the 3 dimensional structure of the protein can be derived using In-silico computational techniques and a target site in the protein can be selected [2]. In influenza viruses, NA surface antigen plays a vital role in releasing the virus from the host cell during the budding stage [3]. Ever since the crystal structure of NA was determined, it is used as a target protein for many drug compounds. Oseltamivir (Figure 1) is one such approved anti-influenza drug compound that targets the highly conserved NA active site of H1N1 Influenza virus which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) [4,5]. The recent outbreaks of H1N1 and reports of oseltamivir resistant strains have necessitated the need to find effective alternatives to the existing anti-influenza drugs [6].


In-Silico screening of Pleconaril and its novel substituted derivatives with Neuraminidase of H1N1 Influenza strain.

Hussain Basha S, Prasad RN - BMC Res Notes (2012)

Structure and properties of Oseltamivir.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369820&req=5

Figure 1: Structure and properties of Oseltamivir.
Mentions: Most of the early antiviral drugs were discovered after screening large number of possible drug compounds using trial and error method. Lately, this approach has been largely replaced by rational drug design, in which, a target viral protein is identified for the drug [1]. A detailed picture of the 3 dimensional structure of the protein can be derived using In-silico computational techniques and a target site in the protein can be selected [2]. In influenza viruses, NA surface antigen plays a vital role in releasing the virus from the host cell during the budding stage [3]. Ever since the crystal structure of NA was determined, it is used as a target protein for many drug compounds. Oseltamivir (Figure 1) is one such approved anti-influenza drug compound that targets the highly conserved NA active site of H1N1 Influenza virus which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) [4,5]. The recent outbreaks of H1N1 and reports of oseltamivir resistant strains have necessitated the need to find effective alternatives to the existing anti-influenza drugs [6].

Bottom Line: 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 variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept. of Biotechnology, REVA Institute of Science and Management, Yelahanka, Bangalore 560064, India. hassainbasha53@gmail.com

ABSTRACT

Background: 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, 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.

Result: 310 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.

Conclusion: Pleconaril variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.

Show MeSH
Related in: MedlinePlus