Computational model of hepatitis B virus DNA polymerase: Molecular dynamics and docking to understand resistant mutations

Abstract

Hepatitis B virus (HBV) DNA polymerase (HDP) is a pharmacological target of intense interest. Of the seven agents approved in USA for the treatment of HBV infections, five are HDP inhibitors. However, resistance development against HDP inhibitors, such as lamivudine and adefovir, has severely hurt their efficacy to treat HBV. As a step toward understanding the mechanism of resistance development and for gaining detailed insights about the active site of the enzyme, we have built a homology model of HDP which is an advance over previously reported ones. Validation using various techniques, including PROSTAT, PROCHECK, and Verify-3D profile, proved the model to be stereochemically significant. The stability of the model was studied using a 5 ns molecular dynamics simulation. The model was found to be sufficiently stable after the initial 2.5 ns with overall root mean squared deviation (RMSD) of 4.13 Å . The homology model matched the results of experimental mutation studies of HDP reported in the literature, including those of antiviral-resistant mutations. Our model suggests the significant role of conserved residues, such as rtLys32, in binding of the inhibitors, contrary to previous studies. The model provides an explanation for the inactivity of some anti-HIV molecules which are inactive against HDP. Conformational changes which occurred in certain binding pocket amino acids helped to explain the better binding of some of the inhibitors in comparison to the substrates.

Extensive Mutagenesis of the Conserved Box E Motif in Duck Hepatitis B Virus P Protein Reveals Multiple Functions in Replication and a Common Structure with the Primer Grip in HIV-1 Reverse Transcriptase

“…Due to its importance as a drug target (all five currently approved chemotherapeutics for hepatitis B virus are nucleos [t]idic RT inhibitors [NRTIs] [31]), several models for the RT domain of the HBV P protein have been calculated by using HIV-1 RT as the template (5,16,17,50). The rationale is the presence in the RT domains of all P proteins of short motifs (boxes A to E plus box F [or box II] and box G [or box I] [ Fig.…”

Molecular Docking Study of Novel Anti-Hepatitis B Virus Agents Isolated from Talaromyces Species

“…The five vanitaracin derivatives obtained from Talaromyces species [23] and three known inhibitors namely entecavir, telbivudine and tenofivir [15] were drawn using sketch molecule function in SYBYLX2.0. The energy minimization of the molecules was performed using Tripos force field and Gasteiger Huckel charge.…”

“…Although HBV infection can be largely prevented by use of effective vaccine, not everyone is vaccinated and there is no vaccine for the people who are already chronically infected. Therefore, there is continuous need for antiviral drugs to suppress viral replication or eliminate infection [15] and antiviral resistance is considered to be one of the most important factors associated with HBV treatment failure [16] and it determines the success of long-term therapy for chronic hepatitis B. Consequently, there is an urgent need to explore novel classes of drugs with different antiviral targets containing anti-HBV agents. Molecular docking plays an important role in drug designing by placing a ligand molecule into the binding site of the target molecule [17] and is demonstrated in the following studies [18][19][20] .…”

Analysis of hepatitis B virus drug-resistant mutation (M204V) using molecular dynamics simulation techniques

“…Homology modelling and flexibility of binding residue by normal mode analysis A homology model of HDP was obtained using previously described methods (Langley et al 2007;Daga et al 2010;Ismail et al 2010;Kim et al 2010). HIV-1 RT shares a sufficient structural and functional similarity with HDP and can serve as a template for modelling the tertiary structure of HDP (Daga et al 2010).…”

“…HIV-1 RT shares a sufficient structural and functional similarity with HDP and can serve as a template for modelling the tertiary structure of HDP (Daga et al 2010). The model for the native HDP was thus constructed with SWISS-MODEL (Schwede et al 2003) using the structure of the HIV-1 RT [Huang et al 1998; Protein Data Bank (PDB) code: 1RTD] as the template structure.…”