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Impact of rtI233V mutation in hepatitis B virus polymerase protein and adefovir efficacy: Homology modeling and molecular docking studies.

Ismail AM, Sharma OP, Kumar MS, Kannangai R, Abraham P - Bioinformation (2013)

Bottom Line: The substitution of isoleucine to valine did not appear to affect the catalytic sites of the protein.In addition, it does not alter the conformation of bent structure formed by residues 235 to 240 that stabilizes the binding of dNTPs.Therefore, it was predicted that rtI233V substitution may not independently affect the antiviral action of adefovir and incoming dNTP binding.

View Article: PubMed Central - PubMed

Affiliation: Departments of Clinical Virology, Christian Medical College, Vellore 632 004, Tamil Nadu, India.

ABSTRACT
Adefovir is an adenosine analogue approved by the Food and Drug Administration for the treatment of chronic hepatitis B. Mutations occurring in the hepatitis B virus (HBV) reverse transcriptase (rt) domains are shown to confer resistance to antiviral drugs. The role of the rtI233V mutation and adefovir resistance remains contradictory. In this study, it was attempted to evaluate the impact of putative rtI233V substitution on adefovir action by homology modeling and docking studies. The HBVrt nucleotide sequence containing rtI233V mutation was obtained from the treatment-naive chronic hepatitis B subject. The three dimensional model of HBV polymerase/rt was constructed using the HIV-1rt template (PDB code: 1RTD A) and the model was evaluated by the Ramachandran plot. Autodock was employed to dock the HBV polymerase/rt and adefovir. The modelled structure showed the amino acid rtI233 to be located away from the drug interactory site. The substitution of isoleucine to valine did not appear to affect the catalytic sites of the protein. In addition, it does not alter the conformation of bent structure formed by residues 235 to 240 that stabilizes the binding of dNTPs. Therefore, it was predicted that rtI233V substitution may not independently affect the antiviral action of adefovir and incoming dNTP binding.

No MeSH data available.


Related in: MedlinePlus

Impact of HBV rtI233V mutation and adefovir binding. Binding conformation of A) wild type (rtI233) and B) mutant(rtI233V) protein-ligand complex derived from Autodock. The ligand (adefovir) and interacting residues are shown in stick formatand red dotted lines represent H-bond. The image was prepared using Chimera 1.6.2 software.
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Figure 1: Impact of HBV rtI233V mutation and adefovir binding. Binding conformation of A) wild type (rtI233) and B) mutant(rtI233V) protein-ligand complex derived from Autodock. The ligand (adefovir) and interacting residues are shown in stick formatand red dotted lines represent H-bond. The image was prepared using Chimera 1.6.2 software.

Mentions: The modelled structure showed the amino acid position rtI233to be located away from the drug interactory site. Thesubstitution of isoleucine to valine did not show to affect thecatalytic sites of aspartate residues at HBVrt positions 83, 205and 206 respectively. However, as observed in the wild type(rtI233) model rtD83, rtD205 and rtN33 did not participate inthe H-bond interaction with the ligand molecule and insteadrtK32 formed H-bonds in the mutant model (Figure 1). Thewild type model exhibited the best docking energy of -5.97Kcal/mol and the rtI233V mutation decreased the dockingscore to less than 1 Kcal/mol (-5.19 Kcal/mol; Table 1 (seesupplementary material). Therefore rtI233V mutation does notshow any significant changes in the binding of adefovir.


Impact of rtI233V mutation in hepatitis B virus polymerase protein and adefovir efficacy: Homology modeling and molecular docking studies.

Ismail AM, Sharma OP, Kumar MS, Kannangai R, Abraham P - Bioinformation (2013)

Impact of HBV rtI233V mutation and adefovir binding. Binding conformation of A) wild type (rtI233) and B) mutant(rtI233V) protein-ligand complex derived from Autodock. The ligand (adefovir) and interacting residues are shown in stick formatand red dotted lines represent H-bond. The image was prepared using Chimera 1.6.2 software.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3569598&req=5

Figure 1: Impact of HBV rtI233V mutation and adefovir binding. Binding conformation of A) wild type (rtI233) and B) mutant(rtI233V) protein-ligand complex derived from Autodock. The ligand (adefovir) and interacting residues are shown in stick formatand red dotted lines represent H-bond. The image was prepared using Chimera 1.6.2 software.
Mentions: The modelled structure showed the amino acid position rtI233to be located away from the drug interactory site. Thesubstitution of isoleucine to valine did not show to affect thecatalytic sites of aspartate residues at HBVrt positions 83, 205and 206 respectively. However, as observed in the wild type(rtI233) model rtD83, rtD205 and rtN33 did not participate inthe H-bond interaction with the ligand molecule and insteadrtK32 formed H-bonds in the mutant model (Figure 1). Thewild type model exhibited the best docking energy of -5.97Kcal/mol and the rtI233V mutation decreased the dockingscore to less than 1 Kcal/mol (-5.19 Kcal/mol; Table 1 (seesupplementary material). Therefore rtI233V mutation does notshow any significant changes in the binding of adefovir.

Bottom Line: The substitution of isoleucine to valine did not appear to affect the catalytic sites of the protein.In addition, it does not alter the conformation of bent structure formed by residues 235 to 240 that stabilizes the binding of dNTPs.Therefore, it was predicted that rtI233V substitution may not independently affect the antiviral action of adefovir and incoming dNTP binding.

View Article: PubMed Central - PubMed

Affiliation: Departments of Clinical Virology, Christian Medical College, Vellore 632 004, Tamil Nadu, India.

ABSTRACT
Adefovir is an adenosine analogue approved by the Food and Drug Administration for the treatment of chronic hepatitis B. Mutations occurring in the hepatitis B virus (HBV) reverse transcriptase (rt) domains are shown to confer resistance to antiviral drugs. The role of the rtI233V mutation and adefovir resistance remains contradictory. In this study, it was attempted to evaluate the impact of putative rtI233V substitution on adefovir action by homology modeling and docking studies. The HBVrt nucleotide sequence containing rtI233V mutation was obtained from the treatment-naive chronic hepatitis B subject. The three dimensional model of HBV polymerase/rt was constructed using the HIV-1rt template (PDB code: 1RTD A) and the model was evaluated by the Ramachandran plot. Autodock was employed to dock the HBV polymerase/rt and adefovir. The modelled structure showed the amino acid rtI233 to be located away from the drug interactory site. The substitution of isoleucine to valine did not appear to affect the catalytic sites of the protein. In addition, it does not alter the conformation of bent structure formed by residues 235 to 240 that stabilizes the binding of dNTPs. Therefore, it was predicted that rtI233V substitution may not independently affect the antiviral action of adefovir and incoming dNTP binding.

No MeSH data available.


Related in: MedlinePlus