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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

A) Homology model of HBV polymerase/rt wild type rtI233 was compared with; B) rtI233V mutation. The relativedistance between the residues 235 to 240 crucial for dNTP binding that form the bent structure is shown as yellow dots.Substitution of valine for isoleucine (rtI233V) reduced its relative distance by only 0.1 Angstrom.
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Figure 2: A) Homology model of HBV polymerase/rt wild type rtI233 was compared with; B) rtI233V mutation. The relativedistance between the residues 235 to 240 crucial for dNTP binding that form the bent structure is shown as yellow dots.Substitution of valine for isoleucine (rtI233V) reduced its relative distance by only 0.1 Angstrom.

Mentions: It has been proposed that residues 235 to 240 form a bentstructure and stabilizes the binding of incoming dNTPs [23].The wild type isoleucine (rtI233) is just located three aminoacids away from the crucial adefovir resistance amino acidposition asparagine (rtN236), which in-part forms the bentstructure. It was further attempted to study whether rtI233Vsubstitution would alter the relative positions of neighbouringresidues and alter the conformation. In wild type model therelative distance of the bent structure formed by the HBVrtamino acids L235, N236, P237, N238, K239 and T240 is 7.8angstrom (Å). Substitution of valine reduced its relativedistance to 7.7 Å. The overall conformation of the bent structureis maintained and the 0.1 Å difference in relative distance maynot impose a spatial constraint to dNTP binding (Figure 2).Therefore, it was predicted that rtI233V substitution in thereverse transcriptase domain may not affect the antiviral actionof adefovir and dNTP binding. Furthermore, two subjects withpre-existing rtI233V mutation at baseline (treatment-naive)responded to lamivudine and entecavir subsequently in ourcenter (unpublished data). This again shows that rtI233Vmutation does not alter the antiviral efficacy to any of thesedrugs.


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)

A) Homology model of HBV polymerase/rt wild type rtI233 was compared with; B) rtI233V mutation. The relativedistance between the residues 235 to 240 crucial for dNTP binding that form the bent structure is shown as yellow dots.Substitution of valine for isoleucine (rtI233V) reduced its relative distance by only 0.1 Angstrom.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: A) Homology model of HBV polymerase/rt wild type rtI233 was compared with; B) rtI233V mutation. The relativedistance between the residues 235 to 240 crucial for dNTP binding that form the bent structure is shown as yellow dots.Substitution of valine for isoleucine (rtI233V) reduced its relative distance by only 0.1 Angstrom.
Mentions: It has been proposed that residues 235 to 240 form a bentstructure and stabilizes the binding of incoming dNTPs [23].The wild type isoleucine (rtI233) is just located three aminoacids away from the crucial adefovir resistance amino acidposition asparagine (rtN236), which in-part forms the bentstructure. It was further attempted to study whether rtI233Vsubstitution would alter the relative positions of neighbouringresidues and alter the conformation. In wild type model therelative distance of the bent structure formed by the HBVrtamino acids L235, N236, P237, N238, K239 and T240 is 7.8angstrom (Å). Substitution of valine reduced its relativedistance to 7.7 Å. The overall conformation of the bent structureis maintained and the 0.1 Å difference in relative distance maynot impose a spatial constraint to dNTP binding (Figure 2).Therefore, it was predicted that rtI233V substitution in thereverse transcriptase domain may not affect the antiviral actionof adefovir and dNTP binding. Furthermore, two subjects withpre-existing rtI233V mutation at baseline (treatment-naive)responded to lamivudine and entecavir subsequently in ourcenter (unpublished data). This again shows that rtI233Vmutation does not alter the antiviral efficacy to any of thesedrugs.

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