Active site binding modes of curcumin in HIV-1 protease and integrase

Vajragupta, Opa; Boonchoong, Preecha; Morris, Garrett M.; Olson, Arthur J.

doi:10.1016/j.bmcl.2005.05.032

Cited by 104 publications

(78 citation statements)

References 22 publications

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“…All water molecules and the 5CITEP were removed while the Mg 2+ at the active site was maintained. The missing residues in the loop at positions 141-144 were incorporated and the polar hydrogen atoms were added to this chain (Vajragupta et al 2005). The second Mg 2+ was placed in the same relative position according to the two metal structures of the Prototype Foamy Virus IN (PDB code 3OYA), a structural homolog of HIV-1 IN (Krishnan and Engelman 2012).…”

Section: Integrase Setupmentioning

confidence: 99%

Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study

Chaniad

Wattanapiromsakul

Pianwanit

et al. 2016

Pharmaceutical Biology

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Context Dioscorea bulbifera L. (Dioscoreaceae) has been used in a traditional Thai longevity medicine preparation. Isolation of inhibitors from natural products is a potential source for continuous development of new HIV-1 integrase (IN) inhibitors. Objective The objective of this study is to isolate the compounds and evaluate their anti-HIV-1 IN activity, as well as to predict the potential interactions of the compounds with an IN. Materials and methods The ethyl acetate and water fractions (1-100 mg/mL) of Dioscorea bulbifera bulbils were isolated and tested for their anti-HIV-1 IN activity using the multiplate integration assay (MIA). The interactions of the active compounds with IN were investigated using a molecular docking method. Results and discussions The ethyl acetate and water fractions of Dioscorea bulbifera bulbils afforded seven compounds. Among these, allantoin (1), 2,4,3 0 ,5 0 -tetrahydroxybibenzyl (2), and 5,7,4 0 -trihydroxy-2-styrylchromone (5) were isolated for the first time from this plant. Myricetin (4) exhibited the most potent activity with an IC 50 value of 3.15 mM, followed by 2,4,6,7-tetrahydroxy-9,10-dihydrophenanthrene (3, IC 50 value¼ 14.20 mM), quercetin-3-O-b-D-glucopyranoside (6, IC 50 value ¼ 19.39 mM) and quercetin-3-O-b-D-galactopyranoside (7, IC 50 value ¼ 21.80 mM). Potential interactions of the active compounds (3, 4, 6, and 7) with the IN active site were additionally investigated. Compound 4 showed the best binding affinity to IN and formed strong interactions with various amino acid residues. These compounds interacted with Asp64, Thr66, His67, Glu92, Asp116, Gln148, Glu152, Asn155, and Lys159, which are involved in both the 3 0 -processing and strand transfer reactions of IN. In particular, galloyl, catechol, and sugar moieties were successful inhibitors for HIV-1 IN.ARTICLE HISTORY

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Section: Integrase Setupmentioning

confidence: 99%

Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study

Chaniad

Wattanapiromsakul

Pianwanit

et al. 2016

Pharmaceutical Biology

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“…All the water molecules and 5CITEP were removed, while a magnesium ion at the active site was maintained. The missing residues in the loop at positions 141-144 were incorporated and polar hydrogen atoms were added to this chain (Vajragupta et al, 2005). The second magnesium ion was placed in the same relative position according to the two metal structures of the Prototype Foamy Virus integrase (PDB code 3OYA), a high structural homolog to HIV-1 IN (Krishnan & Engelman, 2012).…”

Section: Hiv-1 In Preparationmentioning

confidence: 99%

Anti-HIV-1 integrase activity and molecular docking of compounds fromAlbizia procerabark

Panthong

Bunluepuech

Boonnak

et al. 2015

Pharmaceutical Biology

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Context: Albizia procera (Roxb.) Benth. (Mimosaceae) has been traditionally used in Thai longevity preparations. Thus, searching for HIV-1 integrase (HIV-1 IN) agents from natural sources is of interest. Objective: The objective of this study is to examine the inhibitory activity against HIV-1 IN of compounds isolated from the stem bark of Albizia procera. Materials and methods: The EtOH extract and isolated compounds of Albizia procera bark were examined for anti-HIV-1 IN activity at various concentrations (10-100 mg/mL and 10-100 mM) using the multiplate integration assay and molecular docking. Results and discussions:The results showed that the ethanol extract had good anti-HIV-1 IN activity with an IC 50 value of 19.5 mg/mL, whereas ethyl acetate fraction exhibited the most potent with an IC 50 value of 19.1 mg/mL, followed by water fraction (IC 50 value ¼ 21.3 mg/mL), hexane and chloroform fractions (IC 50 value4100 mg/mL), respectively. From bioassay-guided isolation, the ethyl acetate fraction was further separated to give two compounds which are (+)-catechin (1) and protocatechuic acid (2), respectively. Of the tested samples, (+)-catechin (1) exhibited appreciable activity against HIV-1 IN with an IC 50 value of 46.3 mM, whereas protocatechuic acid (2) showed mild activity with 46.0% inhibition at concentration of 100 mM. (+)-Catechin (1) could interact with Thr66, Gly148, and Glu152 in the core domain of IN enzyme, whereas protocatechuic acid (2) could bind with Thr66, His67, Glu152, Asn155, and Lys159. This is the first report on anti-HIV-1 IN activity of Albizia procera bark. These results may suggest that Albizia procera bark has potential as anti-HIV-1 IN agent.

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“…For instance, curcuminoids displayed activity to the HIV-1 protease and integrase enzymes (Vajragupta et al, 2005;Itokawa et al, 2008) and better antifungal activity than fluconazole against Paracoccidioides braziliensis and inhibited adhesion of Candida species to human epithelial cells (Martins et al, 2009). Isoxazole curcuminoids were highly active against mycobacterium tuberculosis (Changtam et al, 2010b).…”

Section: Introductionmentioning

confidence: 99%

Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

et al. 2014

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We have previously reported that curcumin analogs with a C 7 linker bearing a C 4 -C 5 olefinic linker with a single keto group at C3 (enone linker) display midnanomolar activity against the bloodstream form of Trypanosoma brucei. However, no clear indication of their mechanism of action or superior antiparasitic activity relative to analogs with the original di-ketone curcumin linker was apparent. To further investigate their utility as antiparasitic agents, we compare the cellular effects of curcumin and the enone linker lead compound 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (AS-HK014) here. An AS-HK014-resitant line, trypanosomes adapted to AS-HK014 (TA014), was developed by in vitro exposure to the drug. Metabolomic analysis revealed that exposure to AS-HK014, but not curcumin, rapidly depleted glutathione and trypanothione in the wild-type line, although almost all other metabolites were unchanged relative to control. In TA014 cells, thiol levels were similar to untreated wild-type cells and not significantly depleted by AS-HK014. Adducts of AS-HK014 with both glutathione and trypanothione were identified in AS-HK014-exposed wild-type cells and reproduced by chemical reaction. However, adduct accumulation in sensitive cells was much lower than in resistant cells. TA014 cells did not exhibit any changes in sequence or protein levels of glutathione synthetase and g-glutamylcysteine synthetase relative to wild-type cells. We conclude that monoenone curcuminoids have a different mode of action than curcumin, rapidly and specifically depleting thiol levels in trypanosomes by forming an adduct. This adduct may ultimately be responsible for the highly potent trypanocidal and antiparasitic activity of the monoenone curcuminoids.

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Active site binding modes of curcumin in HIV-1 protease and integrase

Cited by 104 publications

References 22 publications

Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study

Anti-HIV-1 integrase compounds from Dioscorea bulbifera and molecular docking study

Anti-HIV-1 integrase activity and molecular docking of compounds fromAlbizia procerabark

Potent Trypanocidal Curcumin Analogs Bearing a Monoenone Linker Motif Act on Trypanosoma brucei by Forming an Adduct with Trypanothione

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