18 research outputs found
Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors
The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world
ntral</Provider><DateDelivered>2013-12-28T14:13:49</DateDelivered><Date plants, part I: a pharmacological evaluation of alkaloids and terpenoids
REVIEW Open Access
The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmacological evaluation of alkaloids and terpenoids Amoa Onguéné et al
Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus
The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development.Medicine, Faculty ofScience, Faculty ofNon UBCBiochemistry and Molecular Biology, Department ofChemistry, Department ofEarth, Ocean and Atmospheric Sciences, Department ofReviewedFacult
Virtualizing the p-ANAPL Library: A Step towards Drug Discovery from African Medicinal Plants
<div><p>Background</p><p>Natural products play a key role in drug discovery programs, both serving as drugs and as templates for the synthesis of drugs, even though the quantities and availabilities of samples for screening are often limitted.</p><p>Experimental approach</p><p>A current collection of physical samples of > 500 compound derived from African medicinal plants aimed at screening for drug discovery has been made by donations from several researchers from across the continent to be directly available for drug discovery programs. A virtual library of 3D structures of compounds has been generated and Lipinskiâs âRule of Fiveâ has been used to evaluate likely oral availability of the samples.</p><p>Results</p><p>A majority of the compound samples are made of flavonoids and about two thirds (2/3) are compliant to the âRule of Fiveâ. The pharmacological profiles of thirty six (36) selected compounds in the collection have been discussed.</p><p>Conclusions and implications</p><p>The p-ANAPL library is the largest physical collection of natural products derived from African medicinal plants directly available for screening purposes. The virtual library is also available and could be employed in virtual screening campaigns.</p></div
Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the number of Lipinski violations, (B) Bar chart showing the MW parameter, (C) Plot of the lipophilicity parameter, (D) Plot of the HBA parameter, (E) Plot of the HBD parameter, and (F) Plot of the NRB parameter.
<p>Distribution of Lipinski parameters for the p-ANAPL library; (A) Bar chart showing the number of Lipinski violations, (B) Bar chart showing the MW parameter, (C) Plot of the lipophilicity parameter, (D) Plot of the HBA parameter, (E) Plot of the HBD parameter, and (F) Plot of the NRB parameter.</p
Chemical structures of selected bioactive natural products from the p-ANAPL library (1 to 7).
<p>Chemical structures of selected bioactive natural products from the p-ANAPL library (1 to 7).</p
Chemical structures of selected bioactive natural products from the p-ANAPL library (14 to 36).
<p>Chemical structures of selected bioactive natural products from the p-ANAPL library (14 to 36).</p
Chemical structures of natural products from the p-ANAPL library with log P > 8 units.
<p>Chemical structures of natural products from the p-ANAPL library with log P > 8 units.</p
Summary of physico-chemical properties (often used to predict âdrug-likenessâ) of the compounds within the p-ANAPL library.
a<p>Library; <i><sup>b</sup></i>Number of tautomers; <i><sup>c</sup></i>Molecular weight; <i><sup>d</sup></i>Logarithm of <i>n</i>-octanol/water partition coefficient; <i><sup>e</sup></i>Number of hydrogen bond acceptors; <i><sup>f</sup></i>Number of hydrogen bond donors; <i><sup>g</sup></i>Number of rotatable single bonds; <i><sup>h</sup></i>Maximum number; <i><sup>i</sup></i>Minimum number; <i><sup>j</sup></i>Mean value; <i><sup>k</sup></i>The âdrug-likeâ library was selected following Lipinskiâs criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Lipinski1" target="_blank">[44]</a>â<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Lipinski2" target="_blank">[45]</a>; <i><sup>l</sup></i>The âlead-likeâ library was selected following Opreaâs criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Teague1" target="_blank">[46]</a>â<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Oprea1" target="_blank">[48]</a>; <i><sup>m</sup></i>The âfragment-likeâ library was selected following Verdonkâs criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Verdonk1" target="_blank">[50]</a>.</p