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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

Molecular surface representations of NS5B binding pocket with top docked ligands.Notes: Conformation of top ligands (binding energy >−9 kcal/mol) inside binding pocket shown by sticks in dim gray. The protein-binding pocket is exposed in molecular surface representation (light blue), with the 12 interacting residues within 4 Å from ligand displayed by green sticks. Docking view of naringenin (A), tryphanthrine (B), dicoumarin (C), swertianin (D), diosmetin (E), apigenin (F), honokiol (G), luteolin (H), and thaliporphine (I).Abbreviation: NS5B, nonstructural protein 5B.
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f3-dddt-9-1825: Molecular surface representations of NS5B binding pocket with top docked ligands.Notes: Conformation of top ligands (binding energy >−9 kcal/mol) inside binding pocket shown by sticks in dim gray. The protein-binding pocket is exposed in molecular surface representation (light blue), with the 12 interacting residues within 4 Å from ligand displayed by green sticks. Docking view of naringenin (A), tryphanthrine (B), dicoumarin (C), swertianin (D), diosmetin (E), apigenin (F), honokiol (G), luteolin (H), and thaliporphine (I).Abbreviation: NS5B, nonstructural protein 5B.

Mentions: The binding pocket was determined by various crystalline structures and binding site prediction servers. A total of 30 ligands with high binding affinities for NS5B were obtained. The docking scores were represented along with hydrogen bonds, direct contacts based on van der Waals (vdW) radii, and interacting residues profiled in Table 2. Binding energies were the representative of how precisely the drug (ligand) binds to the target molecule (protein), and thus were taken as baseline comparison for selection of lead compounds in drug designing. Ninety-three percent of the ligands showed a binding score stronger than 8 kcal/mol on docking with NS5B. None of the ligands showed binding score weaker than −7.4 kcal/mol. Ligands with high affinity scores were naringenin, tryphanthrine, dicoumarin, swertianin, diosmetin, apigenin, honokiol, luteolin, thaliporphine, and oxymatrine. Binding energies of these compounds ranged from −9.7 kcal/mol to −9 kcal/mol, which were stronger as compared to sofosbuvir (−6.2 kcal/mol). These ligands were found to interact mostly with NS5B via Leu392, Ala395, Ala396, His428, and Leu492 residues forming hydrogen and VdW interactions. It is inferred that these interactions stabilize the protein–ligand complex and lead to inhibitory activity on NS5B active site. Among molecular interactions, compounds, namely, naringenin, tryphanthrine, swertianin, diosmetin, luteolin, and thaliporphine were observed to form three hydrogen bonds, each mainly with Ala396 and Arg503. They were also seen to form VdW interactions mainly with His428, Val494, Leu492, Leu392, Pro495, and Ala395 (Table 2). Interestingly, all filtered compounds bind within a narrow groove line with their nonpolar and positively charged residues, and these ligands commonly interact with Val37, Leu392, Ala395, Ala396, His428, Leu492, and Val494 located in this groove (Figure 3). Comprehensively, it can be deduced that Leu492, Leu392, Val494, and Pro495 residues are involved in VdW interactions with NS5B, while Cys146, Ala395, Ala396, His428, and Arg503 are largely involved in forming hydrogen bonds.


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)

Molecular surface representations of NS5B binding pocket with top docked ligands.Notes: Conformation of top ligands (binding energy >−9 kcal/mol) inside binding pocket shown by sticks in dim gray. The protein-binding pocket is exposed in molecular surface representation (light blue), with the 12 interacting residues within 4 Å from ligand displayed by green sticks. Docking view of naringenin (A), tryphanthrine (B), dicoumarin (C), swertianin (D), diosmetin (E), apigenin (F), honokiol (G), luteolin (H), and thaliporphine (I).Abbreviation: NS5B, nonstructural protein 5B.
© Copyright Policy
Related In: Results  -  Collection

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

f3-dddt-9-1825: Molecular surface representations of NS5B binding pocket with top docked ligands.Notes: Conformation of top ligands (binding energy >−9 kcal/mol) inside binding pocket shown by sticks in dim gray. The protein-binding pocket is exposed in molecular surface representation (light blue), with the 12 interacting residues within 4 Å from ligand displayed by green sticks. Docking view of naringenin (A), tryphanthrine (B), dicoumarin (C), swertianin (D), diosmetin (E), apigenin (F), honokiol (G), luteolin (H), and thaliporphine (I).Abbreviation: NS5B, nonstructural protein 5B.
Mentions: The binding pocket was determined by various crystalline structures and binding site prediction servers. A total of 30 ligands with high binding affinities for NS5B were obtained. The docking scores were represented along with hydrogen bonds, direct contacts based on van der Waals (vdW) radii, and interacting residues profiled in Table 2. Binding energies were the representative of how precisely the drug (ligand) binds to the target molecule (protein), and thus were taken as baseline comparison for selection of lead compounds in drug designing. Ninety-three percent of the ligands showed a binding score stronger than 8 kcal/mol on docking with NS5B. None of the ligands showed binding score weaker than −7.4 kcal/mol. Ligands with high affinity scores were naringenin, tryphanthrine, dicoumarin, swertianin, diosmetin, apigenin, honokiol, luteolin, thaliporphine, and oxymatrine. Binding energies of these compounds ranged from −9.7 kcal/mol to −9 kcal/mol, which were stronger as compared to sofosbuvir (−6.2 kcal/mol). These ligands were found to interact mostly with NS5B via Leu392, Ala395, Ala396, His428, and Leu492 residues forming hydrogen and VdW interactions. It is inferred that these interactions stabilize the protein–ligand complex and lead to inhibitory activity on NS5B active site. Among molecular interactions, compounds, namely, naringenin, tryphanthrine, swertianin, diosmetin, luteolin, and thaliporphine were observed to form three hydrogen bonds, each mainly with Ala396 and Arg503. They were also seen to form VdW interactions mainly with His428, Val494, Leu492, Leu392, Pro495, and Ala395 (Table 2). Interestingly, all filtered compounds bind within a narrow groove line with their nonpolar and positively charged residues, and these ligands commonly interact with Val37, Leu392, Ala395, Ala396, His428, Leu492, and Val494 located in this groove (Figure 3). Comprehensively, it can be deduced that Leu492, Leu392, Val494, and Pro495 residues are involved in VdW interactions with NS5B, while Cys146, Ala395, Ala396, His428, and Arg503 are largely involved in forming hydrogen bonds.

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