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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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A) Binding of Best Pleconaril variant (Blue) into the active site of NA. B) Amino acid residues (Yellow) in the active site of NA interacting with Best Pleconaril variant by hydrogen bonds (dotted red line) and pi-cationic interactions (Solid Black line) using -9.97543 K.Cal./mol. of binding energy.
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Figure 6: A) Binding of Best Pleconaril variant (Blue) into the active site of NA. B) Amino acid residues (Yellow) in the active site of NA interacting with Best Pleconaril variant by hydrogen bonds (dotted red line) and pi-cationic interactions (Solid Black line) using -9.97543 K.Cal./mol. of binding energy.

Mentions: 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. Moreover the central benzene ring and furan ring of the best Pleconaril variant played a major role in stabilizing the ligand receptor complex by pi-cation interactions with amino acid residues ARG 118 and ARG 371 along with hydrogen bonds (Figure 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)

A) Binding of Best Pleconaril variant (Blue) into the active site of NA. B) Amino acid residues (Yellow) in the active site of NA interacting with Best Pleconaril variant by hydrogen bonds (dotted red line) and pi-cationic interactions (Solid Black line) using -9.97543 K.Cal./mol. of binding energy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: A) Binding of Best Pleconaril variant (Blue) into the active site of NA. B) Amino acid residues (Yellow) in the active site of NA interacting with Best Pleconaril variant by hydrogen bonds (dotted red line) and pi-cationic interactions (Solid Black line) using -9.97543 K.Cal./mol. of binding energy.
Mentions: 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. Moreover the central benzene ring and furan ring of the best Pleconaril variant played a major role in stabilizing the ligand receptor complex by pi-cation interactions with amino acid residues ARG 118 and ARG 371 along with hydrogen bonds (Figure 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