Structural Studies of Retroviral Integrases

Jaskólski, Mariusz; Alexandratos, Jerry; Bujacz, G.; Wlodawer, Alexander

doi:10.1002/9781118015377.ch4

Cited by 4 publications

(2 citation statements)

References 63 publications

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“…1a). The individual structures of these domains have been characterized for many retroviruses (Jaskolski et al, 2009), but not for PERV. Within the gammaretroviruses, PERV-A/C IN is closely related to MLV IN, sharing 50 % sequence identity in total, with 22 % for the NTD, 72 % for the CCD and 50 % for the CTD.…”

mentioning

confidence: 99%

Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir

Demange

Yajjou-Hamalian

Gallay

et al. 2015

Journal of General Virology

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Porcine endogenous retroviruses (PERVs) are present in the genomes of pig cells. The PERV-A/C recombinant virus can infect human cells and is a major risk of zoonotic disease in the case of xenotransplantation of pig organs to humans. Raltegravir (RAL) is a viral integrase (IN) inhibitor used in highly active antiretroviral treatment. In the present study, we explored the potential use of RAL against PERV-A/C. We report (i) a three-dimensional model of the PERV-A/C intasome complexed with RAL, (ii) the sensitivity of PERV-A/C IN to RAL in vitro and (iii) the sensitivity of a PERV-A/C-IRES-GFP recombinant virus to RAL in cellulo. We demonstrated that RAL is a potent inhibitor against PERV-A/C IN and PERV-A/C replication with IC 50 s in the nanomolar range. To date, the use of retroviral inhibitors remains the only way to control the risk of zoonotic PERV infection during pig-to-human xenotransplantation.

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confidence: 99%

Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir

Demange

Yajjou-Hamalian

Gallay

et al. 2015

Journal of General Virology

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“…Integrases [3] A simplified model of a drug binding to the active site of a large molecule such as a protein is shown in Figure 1. When a drug binds to the active site, the estimated binding energy can be computationally calculated from the energy considerations of the different interactions between the drug and the protein.…”

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confidence: 99%

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Ealy¹,

Abouomar²,

Cogan³

et al. 2017

ABB

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Lipinski's "Rule of Five" was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski's "Rule of Five" was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICMPro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondruglike molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.

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4D-QSAR studies of coumarin derivatives as HIV-1 integrase 3′-processing inhibitors

Patil

Sawant

2015

Med Chem Res

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In a pursuit of combating acquired immunodeficiency syndrome, the targets human immunodeficiency virus (HIV) protease, reverse transcriptase and HIV specific proteins were exhaustively explored. Resistance through mutations in these targets has impeded the further developments in HIV research. HIV-1 integrase (HIV-1 IN) has emerged as a newer target and 3 0 -processing, and strand transfer inhibition has proved potential intervention in HIV replication. In present study, in line with our interests in coumarin derivatives as potential bioactive molecules, 4D-quantitative structure-activity relationship (4D-QSAR) is proposed. Fifty-seven structurally diverse coumarin derivatives were subjected to 4D-QSAR studies. Quantum mechanics-based geometry optimization and molecular dynamics simulation were carried out on individual compound. The conformational ensemble generated for each compound was aligned with most active compound, and Coulombic and Lennard-Jones interaction energy descriptors were computed. After selecting the best variables in MATLAB, partial least square regression (PLS) analysis was carried out on 44 training set and 13 test set compounds. The model with ten latent variables was found best with R 2 calculated = 0.903015, R 2 crossvalidated = 0.599553, R 2 predicted = 0.688525, rootmean-square error (RMSE) calculated = 0.21276, RMSE predicted = 0.371579 and prediction bias = -0.15362. Docking studies were carried out on AutoDock Vina, which were in good agreement with the PLS model, suggesting the importance of few descriptors of Coulombic interaction energy and VWD interactions with VAL79, VAL77, ARG199 and GLU157. These results may be useful in designing more potent HIV-1 IN inhibitors.

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Structural Studies of Retroviral Integrases

Cited by 4 publications

References 63 publications

Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir

Porcine endogenous retrovirus-A/C: biochemical properties of its integrase and susceptibility to raltegravir

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

4D-QSAR studies of coumarin derivatives as HIV-1 integrase 3′-processing inhibitors

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