Prediction of HIV-1 Integrase/Viral DNA Interactions in the Catalytic Domain by Fast Molecular Docking

2004 ◽  
Vol 47 (4) ◽  
pp. 821-828 ◽  
Author(s):  
Adeyemi A. Adesokan ◽  
Victoria A. Roberts ◽  
Keun Woo Lee ◽  
Roberto D. Lins ◽  
James M. Briggs
Keyword(s):  
Molecular Docking ◽  
Catalytic Domain ◽  
Dna Interactions ◽  
Viral Dna ◽  
Hiv 1

scholarly journals The Effect of Geometrical Isomerism of 3,5-Dicaffeoylquinic Acid on Its Binding Affinity to HIV-Integrase Enzyme: A Molecular Docking Study

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mpho M. Makola ◽  
Ian A. Dubery ◽  
Gerrit Koorsen ◽  
Paul A. Steenkamp ◽  
Mwadham M. Kabanda ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Density Functional ◽  
Catalytic Domain ◽  
Synergistic Activity ◽  
Hiv Integrase ◽  
Molecular Docking Study ◽  
Geometrical Isomers ◽  
Catalytic Core ◽  
Dicaffeoylquinic Acid ◽  
Hiv 1

A potent plant-derived HIV-1 inhibitor, 3,5-dicaffeoylquinic acid (diCQA), has been shown to undergo isomerisation upon UV exposure where the naturally occurring3trans,5trans-diCQA isomer gives rise to the3cis,5trans-diCQA,3trans,5cis-diCQA, and3cis,5cis-diCQA isomers. In this study, inhibition of HIV-1 INT by UV-induced isomers was investigated using molecular docking methods. Here, density functional theory (DFT) models were used for geometry optimization of the 3,5-diCQA isomers. The YASARA and Autodock VINA software packages were then used to determine the binding interactions between the HIV-1 INT catalytic domain and the 3,5-diCQA isomers and the Discovery Studio suite was used to visualise the interactions between the isomers and the protein. The geometrical isomers of 3,5-diCQA were all found to bind to the catalytic core domain of the INT enzyme. Moreover, thecisgeometrical isomers were found to interact with the metal cofactor of HIV-1INT, a phenomenon which has been linked to antiviral potency. Furthermore, the3trans,5cis-diCQA isomer was also found to interact with both LYS156 and LYS159 which are important residues for viral DNA integration. The differences in binding modes of these naturally coexisting isomers may allow wider synergistic activity which may be beneficial in comparison to the activities of each individual isomer.

scholarly journals APOBEC3F and APOBEC3G Inhibit HIV-1 DNA Integration by Different Mechanisms

2010 ◽  
Vol 84 (10) ◽  
pp. 5250-5259 ◽  
Author(s):  
Jean L. Mbisa ◽  
Wei Bu ◽  
Vinay K. Pathak
Keyword(s):  
Catalytic Domain ◽  
Restriction Factors ◽  
Viral Dna ◽  
Dna Integration ◽  
Host Restriction ◽  
Antiviral Activities ◽  
Viral Cdna ◽  
Viral Dna Integration ◽  
Cytidine Deamination ◽  
Hiv 1

ABSTRACT APOBEC3F (A3F) and APBOBEC3G (A3G) both are host restriction factors that can potently inhibit human immunodeficiency virus type 1 (HIV-1) replication. Their antiviral activities are at least partially mediated by cytidine deamination, which causes lethal mutations of the viral genome. We recently showed that A3G blocks viral plus-strand DNA transfer and inhibits provirus establishment in the host genome (J. L. Mbisa, R. Barr, J. A. Thomas, N. Vandegraaff, I. J. Dorweiler, E. S. Svarovskaia, W. L. Brown, L. M. Mansky, R. J. Gorelick, R. S. Harris, A. Engelman, and V. K. Pathak, J. Virol. 81:7099-7110, 2007). Here, we investigated whether A3F similarly interferes with HIV-1 provirus formation. We observed that both A3F and A3G inhibit viral DNA synthesis and integration, but A3F is more potent than A3G in preventing viral DNA integration. We further investigated the mechanisms by which A3F and A3G block viral DNA integration by analyzing their effects on viral cDNA processing using Southern blot analysis. A3G generates a 6-bp extension at the viral U5 end of the 3′ long terminal repeat (3′-LTR), which is a poor substrate for integration; in contrast, A3F inhibits viral DNA integration by reducing the 3′ processing of viral DNA at both the U5 and U3 ends. Furthermore, we demonstrated that a functional C-terminal catalytic domain is more critical for A3G than A3F function in blocking HIV-1 provirus formation. Finally, we showed that A3F has a greater binding affinity for a viral 3′-LTR double-stranded DNA (dsDNA) oligonucleotide template than A3G. Taking these results together, we demonstrated that mechanisms utilized by A3F to prevent HIV-1 viral DNA integration were different from those of A3G, and that their target specificities and/or their affinities for dsDNA may contribute to their distinct mechanisms.

scholarly journals Probing of HIV-1 Integrase/DNA Interactions Using Novel Analogs of Viral DNA

2006 ◽  
Vol 281 (17) ◽  
pp. 11530-11540 ◽  
Author(s):  
Julia Agapkina ◽  
Maksim Smolov ◽  
Sophie Barbe ◽  
Evgenii Zubin ◽  
Timofei Zatsepin ◽  
...  
Keyword(s):  
Dna Interactions ◽  
Viral Dna ◽  
Hiv 1

Molecular Docking, Synthesis and anti-HIV-1 Protease Activity of Novel Chalcones

2020 ◽  
Vol 26 (8) ◽  
pp. 802-814 ◽  
Author(s):  
Nemanja Turkovic ◽  
Branka Ivkovic ◽  
Jelena Kotur-Stevuljevic ◽  
Milica Tasic ◽  
Bojan Marković ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Molecular Docking ◽  
Chemical Synthesis ◽  
Protease Activity ◽  
Molecular Mechanisms ◽  
Replication Cycle ◽  
Low Molecular Weight ◽  
Chalcone Derivatives ◽  
Anti Hiv ◽  
Hiv 1

Background: Since the beginning of the HIV/AIDS epidemic, 75 million people have been infected with the HIV and about 32 million people have died of AIDS. Investigation of the molecular mechanisms critical to the HIV replication cycle led to the identification of potential drug targets for AIDS therapy. One of the most important discoveries is HIV-1 protease, an enzyme that plays an essential role in the replication cycle of HIV. Objective: The aim of the present study is to synthesize and investigate anti-HIV-1 protease activity of some chalcone derivatives with the hope of discovering new lead structure devoid drug resistance. Methods: 20 structurally similar chalcone derivatives were synthesized and their physico-chemical characterization was performed. Binding of chalcones to HIV-1 protease was investigated by fluorimetric assay. Molecular docking studies were conducted to understand the interactions. Results: The obtained results revealed that all compounds showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity with an IC50 value of 0.001 μM, which is comparable with commercial product Darunavir. Conclusion: It is difficult to provide general principles of inhibitor design. Structural properties of the compounds are not the only consideration; ease of chemical synthesis, low molecular weight, bioavailability, and stability are also of crucial importance. Compared to commercial products the main advantage of compound C1 is the ease of chemical synthesis and low molecular weight. Furthermore, compound C1 has a structure that is different to peptidomimetics, which could contribute to its stability and bioavailability.

scholarly journals Evaluation of a System to Screen for Stimulators of Non-Specific DNA Nicking by HIV-1 Integrase: Application to a Library of 50,000 Compounds

2011 ◽  
Vol 22 (2) ◽  
pp. 67-74 ◽  
Author(s):  
Malgorzata Sudol ◽  
Jennifer L Fritz ◽  
Melissa Tran ◽  
Gavin P Robertson ◽  
Julie B Ealy ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Solution Phase ◽  
The Novel ◽  
Endonuclease Activity ◽  
Viral Dna ◽  
Hit Rate ◽  
Dna Nicking ◽  
Hiv 1 ◽  
Stimulation Of

Background: In addition to activities needed to catalyse integration, retroviral integrases exhibit non-specific endonuclease activity that is enhanced by certain small compounds, suggesting that integrase could be stimulated to damage viral DNA before integration occurs. Methods: A non-radioactive, plate-based, solution phase, fluorescence assay was used to screen a library of 50,080 drug-like chemicals for stimulation of non-specific DNA nicking by HIV-1 integrase. Results: A semi-automated workflow was established and primary hits were readily identified from a graphic output. Overall, 0.6% of the chemicals caused a large increase in fluorescence (the primary hit rate) without also having visible colour that could have artifactually caused this result. None of the potential stimulators from this moderate-size library, however, passed a secondary test that included an inactive integrase mutant that assessed whether the increased fluorescence depended on the endonuclease activity of integrase. Conclusions: This first attempt at identifying integrase stimulator compounds establishes the necessary logistics and workflow required. The results from this study should encourage larger scale high-throughput screening to advance the novel antiviral strategy of stimulating integrase to damage retroviral DNA.

3D-QSAR, molecular docking and in silico ADMET studies of propiophenone derivatives with anti-HIV-1 protease activity

2021 ◽  
Author(s):  
Milan Jovanović ◽  
Nemanja Turković ◽  
Branka Ivković ◽  
Zorica Vujić ◽  
Katarina Nikolić ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Protease Activity ◽  
3D Qsar ◽  
In Silico Admet ◽  
Anti Hiv ◽  
Hiv 1

Synthesis, Biological Evaluation, and Molecular Docking Studies of Novel 4-[4-Arylpyridin-1(4H)-yl]benzoic Acid Derivatives as Anti-HIV-1 Agents

2017 ◽  
Vol 14 (12) ◽  
pp. e1700295 ◽  
Author(s):  
Saghi Sepehri ◽  
Sepehr Soleymani ◽  
Rezvan Zabihollahi ◽  
Mohammad R. Aghasadeghi ◽  
Mehdi Sadat ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Benzoic Acid ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molecular Docking Studies ◽  
Benzoic Acid Derivatives ◽  
Anti Hiv ◽  
Hiv 1

Model of full-length HIV-1 integrase complexed with viral DNA as template for anti-HIV drug design

2004 ◽  
Vol 18 (12) ◽  
pp. 739-760 ◽  
Author(s):  
Rajeshri G. Karki ◽  
Yun Tang ◽  
Terrence R. Burke ◽  
Marc C. Nicklaus
Keyword(s):  
Drug Design ◽  
Full Length ◽  
Viral Dna ◽  
Anti Hiv ◽  
Hiv 1
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