In-Silico docking of HIV-1 integrase inhibitors reveals a novel drug type acting on an enzyme/DNA reaction intermediate

Savarino, Andrea

doi:10.1186/1742-4690-4-21

Cited by 73 publications

(78 citation statements)

References 44 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, Savarino (31) reported an in silico docking simulation of HIV-1 IN with several IN inhibitors, including EVG. The model was derived from an X-ray structure of 5CITEP [1-(5-chloroindol-3-yl)-3-(tetrazoyl)-1,3-propandione-ene] bound to the catalytic core domain of IN (16), with two magnesium ions into the active site.…”

Section: Discussionmentioning

confidence: 99%

Resistance Mutations in Human Immunodeficiency Virus Type 1 Integrase Selected with Elvitegravir Confer Reduced Susceptibility to a Wide Range of Integrase Inhibitors

Goethals¹,

Clayton²,

Ginderen³

et al. 2008

J Virol

149

112

View full text Add to dashboard Cite

Integration of viral DNA into the host chromosome is an essential step in the life cycle of retroviruses and is facilitated by the viral integrase enzyme. The first generation of integrase inhibitors recently approved or currently in late-stage clinical trials shows great promise for the treatment of human immunodeficiency virus (HIV) infection, but virus is expected to develop resistance to these drugs. Therefore, we used a novel resistance selection protocol to follow the emergence of resistant HIV in the presence of the integrase inhibitor elvitegravir (GS-9137). We find the primary resistance-conferring mutations to be Q148R, E92Q, and T66I and demonstrate that they confer a reduction in susceptibility not only to elvitegravir but also to raltegravir (MK-0518) and other integrase inhibitors. The locations of the mutations are highlighted in the catalytic sites of integrase, and we correlate the mutations with expected drug-protein contacts. In addition, mutations that do not confer reduced susceptibility when present alone (H114Y, L74M, R20K, A128T, E138K, and S230R) are also discussed in relation to their position in the catalytic core domain and their proximity to known structural features of integrase. These data broaden the understanding of antiviral resistance against integrase inhibitors and may give insight facilitating the discovery of second-generation compounds.Integration of retroviral DNA is an essential step in the life cycle of human immunodeficiency virus (HIV) (29). The integration process is facilitated by the viral integrase (IN) enzyme which catalyzes the insertion of the viral DNA into the host genome in a multistep process involving viral and host proteins. HIV IN recognizes and binds specific sequences in the long terminal repeats (LTRs) of the viral retrotranscribed DNA in the cytoplasm. After DNA binding, IN cleaves GT dinucleotides from the 3Ј termini of the linear cDNA in a process called 3Ј processing (2). The processed viral DNA, as part of the preintegration complex, is then translocated into the nucleus, where IN inserts the viral DNA into the host chromosome by a process called strand transfer (2,12,13). There are few cellular enzymes with comparable function to HIV integrase (24), apart from the V(D)J polynucleotide recombinase RAG1 (34). Therefore, the IN enzyme has been considered an attractive target for antiretroviral therapy for the last decade (27, 36). Recent progress has resulted in two IN inhibitors (5, 30), with one drug in late-stage clinical trials and one currently approved for use in treatment-experienced patients (18). For all currently targeted retroviral proteins, inhibition with antiretroviral drugs has led to emergence of resistance in treated patients, often leading to treatment failure and requiring changes in the composition of the highly active antiretroviral therapy (HAART) drug regimen (6). Nevertheless, the emergence of new classes of drugs will enable new combinations of inhibitors to be used and will offer more treatment options to HIV-infected pati...

show abstract

Section: Discussionmentioning

confidence: 99%

Resistance Mutations in Human Immunodeficiency Virus Type 1 Integrase Selected with Elvitegravir Confer Reduced Susceptibility to a Wide Range of Integrase Inhibitors

Goethals¹,

Clayton²,

Ginderen³

et al. 2008

J Virol

149

112

View full text Add to dashboard Cite

show abstract

“…A three-dimensional model of EVG in complex with HIV-1 IN CCD was prepared by PyMOL software, version 0.97, using previously reported data (44). Amino acid residues involved in resistance to EVG were displayed within this model.…”

Section: Methodsmentioning

confidence: 99%

Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137)

Shimura

Kodama

Sakagami

et al. 2008

J Virol

308

255

View full text Add to dashboard Cite

show abstract

“…A two-metal model for HIV-1 IN CCD in complex with the small molecule, 1-(5-chloroindol-3-yl)-3-(tetrazoyl)-1,3-propandione-ene (5-CITEP), was used as a surrogate for an IN/ viral DNA complex, as this model explains the molecular recognition interactions. 28 The molecular docking poses along with interactive sites of the compounds with amino acids are provided (Supporting Table S1). The molecular docking study of 4m, 6c, and 6d demonstrated that nitro groups chelate with both the active site magnesium ions.…”

mentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

Tandon

Urvashi

Yadav

et al. 2015

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

6-Endo-dig-cyclization is an efficient method for the synthesis of 1,2-dihydroisoquinolines. We have synthesized few 1,2-dihydroisoquinolines having different functionality at the C-1, C-3, C-7, and N-2 positions for evaluation against HIV-1 integrase (HIV1-IN) inhibitory activity. A direct nitro-Mannich condensation of o-alkynylaldimines and dual activation of o-alkynyl aldehydes by inexpensive cobalt chloride yielded desired compounds. Out of 24 compounds, 4m and 6c came out as potent integrase inhibitors in in vitro strand transfer (ST) assay, with IC 50 value of 0.7 and 0.8 μM, respectively. Molecular docking of these compounds in integrase revealed strong interaction between metal and ligands, which stabilizes the enzyme−inhibitor complex. The ten most active compounds were subjected to antiviral assay. Out of those, 6c reduced the level of p24 viral antigen by 91%, which is comparable to RAL in antiviral assay. Interestingly, these compounds showed similar ST inhibitory activity in G140S mutant, suggesting they can act against resistant strains.

show abstract

In-Silico docking of HIV-1 integrase inhibitors reveals a novel drug type acting on an enzyme/DNA reaction intermediate

Cited by 73 publications

References 44 publications

Resistance Mutations in Human Immunodeficiency Virus Type 1 Integrase Selected with Elvitegravir Confer Reduced Susceptibility to a Wide Range of Integrase Inhibitors

Resistance Mutations in Human Immunodeficiency Virus Type 1 Integrase Selected with Elvitegravir Confer Reduced Susceptibility to a Wide Range of Integrase Inhibitors

Broad Antiretroviral Activity and Resistance Profile of the Novel Human Immunodeficiency Virus Integrase Inhibitor Elvitegravir (JTK-303/GS-9137)

Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors

Contact Info

Product

Resources

About