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. 2023 Jun 7:3:1123307.
doi: 10.3389/fbinf.2023.1123307. eCollection 2023.

Human adenovirus DNA polymerase is evolutionarily and functionally associated with human telomerase reverse transcriptase based on in silico molecular characterization that implicate abacavir and zidovudine

Toluwase Hezekiah Fatoki  1
Affiliations

Human adenovirus DNA polymerase is evolutionarily and functionally associated with human telomerase reverse transcriptase based on in silico molecular characterization that implicate abacavir and zidovudine

Toluwase Hezekiah Fatoki. Front Bioinform. .

Abstract

Human adenoviruses (HAdVs) are non-enveloped, small double stranded DNA (dsDNA) viruses that cause asymptomatic infections, clinical syndromes and significant susceptibility to infections in immunocompromised people. The aim of the present study was to identify critical host proteins and HAdV hypothetical proteins that could be developed as potential host-viral targets for antiHAdV therapy. Here, the function of selected hypothetical proteins of HAdV based on phylogenetic relationship with the therapeutic targets of antiretroviral drugs of human immunodeficiency virus (HIV) was predicted computationally, and characterized the molecular dynamics and binding affinity of DNA polymerase of HAdV. Thirty-eight hypothetical proteins (HPs) of human adenovirus (HAdV) were used in this study. The results showed that HAdV DNA polymerase (P03261) is related to Human TERT (O14746) and HLA-B (P01889) genes. The protein-protein interaction of human five molecular targets (PNP, TERT, CCR5, HLA-B, and NR1I2) of ARVDs are well-coordinated/networked with CD4, AHR, FKBP4, NR3C1, HSP90AA1, and STUB1 proteins in the anti-HIV infection mechanism. The results showed that the free energy score of abacavir and zidovudine binding to HAdV DNA polymerase are -5.8 and -5.4 kcal mol-1 respectively. Also, the control drug, cidofovir and ganciclovir have less binding affinity for DNA polymerase of HAdV when compare to that of abacavir and zidovudine. Similarity was observed in the binding of abacavir and zidovudine to HAdV DNA polymerase (ASP742, ALA743, LEU772, ARG773 and VAL776). In conclusion, combination of abacavir and zidovudine was predicted to be potential therapy for controlling HAdV infection targeting HAdV DNA polymerase.

Keywords: DNA polymerase; antiretroviral drugs; human adenoviruses (HAdVs); hypothetical proteins; molecular dynamics and docking.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Phylogentic tree of the 14 ARVDs molecular targets (colored stars) together with 38 hypothetical proteins of HAV.
FIGURE 2
FIGURE 2
The relationship between (A) HAdV DNA Pol protein (UniProt ID: P03261) and human TERT protein (UniProt ID: O14746), (B) HAdV DNA Pol protein (UniProt ID: P03261) and human HLA-B protein (UniProt ID: P01889).
FIGURE 3
FIGURE 3
Expanded protein-protein interaction of five molecular targets (PNP, TERT, CCR5, HLA-B, and NR1I2) of ARVDs in human.
FIGURE 4
FIGURE 4
Gene network interactions of human metabolic genes impacted by ARVDs.
FIGURE 5
FIGURE 5
Structure of seven multitargeted anti-HIV drugs together with two anti-HHV drugs (cidofovir and ganciclovir).
FIGURE 6
FIGURE 6
2D structure of binding interaction of (A) 2JLE-Abacavir complex. (B) 2JLE-Zidovudine complex. (C) AF-P01889-Abacavir complex. (D) Model_P03261-Abacavir complex. (E) Model_P03261-Zidovudine complex. (F) AF-O14746-Zidovudine complex.
FIGURE 7
FIGURE 7
3D structure of binding interaction of (A) 2JLE-Abacavir complex. (B) 2JLE-Zidovudine complex. (C) AF-P01889-Abacavir complex. (D) Model_P03261-Abacavir complex. (E) Model_P03261-Zidovudine complex. (F) AF-O14746-Zidovudine complex.
FIGURE 8
FIGURE 8
The structural characteristics of HAdV hypothetical protein DNA polymerase (PDB ID: model_P03261): (A) CABSFlex2 superimposition of 10 model structures (B) SWAXS net intensity Guinier fit. (C) Simulated RMSF of free protein using CABSFlex2 server (D) Simulated RMSF in the presence of Abacavir using Desmond (E) Simulated RMSF in the presence of zidovudine using Desmond.
FIGURE 9
FIGURE 9
MDS results (A) RMSD plot of HAdV DNA pol (PDB ID: model_P03261) in complex with Abacavir (B) RMSD plot of HAdV DNA pol (PDB ID: model_P03261) in complex with Zidovudine (C) Rg of HAdV DNA pol (PDB ID: model_P03261) in the presence of Abacavir. (D) Rg of HAdV DNA pol (PDB ID: model_P03261) in the presence of Zidovudine.
FIGURE 10
FIGURE 10
MDS results (A) Sub-energy interaction of HAdV DNA pol (PDB ID: model_P03261) in complex with Abacavir. (B) Sub-energy interaction of HAdV DNA pol (PDB ID: model_P03261) in complex with Zidovudine. (C) SASA of HAdV DNA pol (PDB ID: model_P03261) in the presence of Abacavir. (D) SASA of HAdV DNA pol (PDB ID: model_P03261) in the presence of Zidovudine.
FIGURE 11
FIGURE 11
Principal component analysis results of (A) HAdV DNA pol (PDB ID: model_P03261) in complex with Abacavir. (B) HAdV DNA pol (PDB ID: model_P03261) in complex with Zidovudine.
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