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

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The potential of anti-malarial compounds derived from African medicinal plants. Part I: A pharmacological evaluation of alkaloids and terpenoids Amoa Onguéné et al

Molecular Modeling of Potential Anticancer Agents from African Medicinal Plants

Naturally occurring anticancer compounds represent about half of the chemotherapeutic drugs which have been put in the market against cancer until date. Computer-based or <i>in silico</i> virtual screening methods are often used in lead/hit discovery protocols. In this study, the “drug-likeness” of ∼400 compounds from African medicinal plants that have shown <i>in vitro</i> and/or <i>in vivo</i> anticancer, cytotoxic, and antiproliferative activities has been explored. To verify potential binding to anticancer drug targets, the interactions between the compounds and 14 selected targets have been analyzed by <i>in silico</i> modeling. Docking and binding affinity calculations were carried out, in comparison with known anticancer agents comprising ∼1 500 published naturally occurring plant-based compounds from around the world. The results reveal that African medicinal plants could represent a good starting point for the discovery of anticancer drugs. The small data set generated (named AfroCancer) has been made available for research groups working on virtual screening

Distibution curves for some computed ADME parameters.

<p>(A) logB/B, (B) log<i>K</i>_HSA, (C) logHERG. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. −2 is equivalent to −2 to −1. The colour codes are according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0078085#pone-0078085-g005" target="_blank">Figure 5</a>.</p

Summary of average predicted pharmacokinetic property distributions of the total AfroDb library in comparison with the various subsets.

<p>Summary of average predicted pharmacokinetic property distributions of the total AfroDb library in comparison with the various subsets.</p

2D structures of the three compounds with log <i>P</i> values >14, included in AfroDb.

<p>2D structures of the three compounds with log <i>P</i> values >14, included in AfroDb.</p

2D structures of selected promising compounds derived from the African flora and included in AfroDb.

<p>2D structures of selected promising compounds derived from the African flora and included in AfroDb.</p

Pairwise comparison of mutual relationships between molecular descriptors.

<p>(A) The distribution of the calculated log <i>P</i> versus MW, (B) HBA against MW, (C) HBD against MW and (D) NRB versus MW. LCR represents the Lipinski compliant regions.</p

Comparison of property distribution for the two datasets by percentage distributions.

<p>(A) MW, (B) log <i>P</i>, (C) HBA and (D) HBD. DNP in red and AfroDb in blue. For subfigure B, the <i>x</i>-axis label is the lower limit of binned data, e.g. −2 is equivalent to −2 to −1.</p