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Pharmacoinformatics approach for investigation of alternative potential hepatitis C virus nonstructural protein 5B inhibitors.

Mirza MU, Ghori NU, Ikram N, Adil AR, Manzoor S - Drug Des Devel Ther (2015)

Bottom Line: Hence, there is an urgent need to scrutinize alternate therapies against HCV that are available at affordable price and do not have associated side effects.The results were compared to docking results of sofosbuvir.The results showed the potential alternative lead compounds that can be developed into commercial drugs having high binding energy and promising ADMET properties.

View Article: PubMed Central - PubMed

Affiliation: Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan.

ABSTRACT
Hepatitis C virus (HCV) is one of the major viruses affecting the world today. It is a highly variable virus, having a rapid reproduction and evolution rate. The variability of genomes is due to hasty replication catalyzed by nonstructural protein 5B (NS5B) which is also a potential target site for the development of anti-HCV agents. Recently, the US Food and Drug Administration approved sofosbuvir as a novel oral NS5B inhibitor for the treatment of HCV. Unfortunately, it is much highlighted for its pricing issues. Hence, there is an urgent need to scrutinize alternate therapies against HCV that are available at affordable price and do not have associated side effects. Such a need is crucial especially in underdeveloped countries. The search for various new bioactive compounds from plants is a key part of pharmaceutical research. In the current study, we applied a pharmacoinformatics-based approach for the identification of active plant-derived compounds against NS5B. The results were compared to docking results of sofosbuvir. The lead compounds with high-binding ligands were further analyzed for pharmacokinetic and pharmacodynamic parameters based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. The results showed the potential alternative lead compounds that can be developed into commercial drugs having high binding energy and promising ADMET properties.

No MeSH data available.


Related in: MedlinePlus

An inside view of binding pocket of HCV-NS5B, with a small drug molecule (naringenin) firmly bound.Note: Interpolated charge (color intensity from blue to red) of binding pocket residues (in sticks) is represented.Abbreviations: HCV, hepatitis C virus; NS5B, nonstructural protein 5B.
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f2-dddt-9-1825: An inside view of binding pocket of HCV-NS5B, with a small drug molecule (naringenin) firmly bound.Note: Interpolated charge (color intensity from blue to red) of binding pocket residues (in sticks) is represented.Abbreviations: HCV, hepatitis C virus; NS5B, nonstructural protein 5B.

Mentions: The protein-binding site prediction servers validated the binding site residues of target protein. A superimposition of all five complexes further confirmed the most conserved interacting amino acids of NS5B (Figure 1). It was found that nine amino acids were actually involved in interactions with HCV-NS5B inhibitors. These interacting residues include Val37, Leu492, His428, Ala395, Leu392, Val494, Ala396, Arg503, Ile424, and Pro495, constituting the active site for HCV-NS5B. Furthermore, a deep groove, encompassing the binding pocket, was observed, thus providing space for inhibitors to strongly bind with the active site of NS5B (Figure 2). It was assumed that binding of drug in this deep groove will inhibit virus from replication, and it seems to be a promising mode of action to be chosen for designing drug candidates against HCV.


Pharmacoinformatics approach for investigation of alternative potential hepatitis C virus nonstructural protein 5B inhibitors.

Mirza MU, Ghori NU, Ikram N, Adil AR, Manzoor S - Drug Des Devel Ther (2015)

An inside view of binding pocket of HCV-NS5B, with a small drug molecule (naringenin) firmly bound.Note: Interpolated charge (color intensity from blue to red) of binding pocket residues (in sticks) is represented.Abbreviations: HCV, hepatitis C virus; NS5B, nonstructural protein 5B.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383224&req=5

f2-dddt-9-1825: An inside view of binding pocket of HCV-NS5B, with a small drug molecule (naringenin) firmly bound.Note: Interpolated charge (color intensity from blue to red) of binding pocket residues (in sticks) is represented.Abbreviations: HCV, hepatitis C virus; NS5B, nonstructural protein 5B.
Mentions: The protein-binding site prediction servers validated the binding site residues of target protein. A superimposition of all five complexes further confirmed the most conserved interacting amino acids of NS5B (Figure 1). It was found that nine amino acids were actually involved in interactions with HCV-NS5B inhibitors. These interacting residues include Val37, Leu492, His428, Ala395, Leu392, Val494, Ala396, Arg503, Ile424, and Pro495, constituting the active site for HCV-NS5B. Furthermore, a deep groove, encompassing the binding pocket, was observed, thus providing space for inhibitors to strongly bind with the active site of NS5B (Figure 2). It was assumed that binding of drug in this deep groove will inhibit virus from replication, and it seems to be a promising mode of action to be chosen for designing drug candidates against HCV.

Bottom Line: Hence, there is an urgent need to scrutinize alternate therapies against HCV that are available at affordable price and do not have associated side effects.The results were compared to docking results of sofosbuvir.The results showed the potential alternative lead compounds that can be developed into commercial drugs having high binding energy and promising ADMET properties.

View Article: PubMed Central - PubMed

Affiliation: Centre for Research in Molecular Medicine (CRiMM), The University of Lahore, Lahore, Pakistan.

ABSTRACT
Hepatitis C virus (HCV) is one of the major viruses affecting the world today. It is a highly variable virus, having a rapid reproduction and evolution rate. The variability of genomes is due to hasty replication catalyzed by nonstructural protein 5B (NS5B) which is also a potential target site for the development of anti-HCV agents. Recently, the US Food and Drug Administration approved sofosbuvir as a novel oral NS5B inhibitor for the treatment of HCV. Unfortunately, it is much highlighted for its pricing issues. Hence, there is an urgent need to scrutinize alternate therapies against HCV that are available at affordable price and do not have associated side effects. Such a need is crucial especially in underdeveloped countries. The search for various new bioactive compounds from plants is a key part of pharmaceutical research. In the current study, we applied a pharmacoinformatics-based approach for the identification of active plant-derived compounds against NS5B. The results were compared to docking results of sofosbuvir. The lead compounds with high-binding ligands were further analyzed for pharmacokinetic and pharmacodynamic parameters based on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. The results showed the potential alternative lead compounds that can be developed into commercial drugs having high binding energy and promising ADMET properties.

No MeSH data available.


Related in: MedlinePlus