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 Lipinski’s “Rule of Five” 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 “Rule of Five”. 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

Summary of physico-chemical properties (often used to predict ‘drug-likeness’) of the compounds within the p-ANAPL library.

a<p>Library; <i>^b</i>Number of tautomers; <i>^c</i>Molecular weight; <i>^d</i>Logarithm of <i>n</i>-octanol/water partition coefficient; <i>^e</i>Number of hydrogen bond acceptors; <i>^f</i>Number of hydrogen bond donors; <i>^g</i>Number of rotatable single bonds; <i>^h</i>Maximum number; <i>ⁱ</i>Minimum number; <i>^j</i>Mean value; <i>^k</i>The “drug-like” library was selected following Lipinski’s criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Lipinski1" target="_blank">[44]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Lipinski2" target="_blank">[45]</a>; <i>^l</i>The “lead-like” library was selected following Oprea’s criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Teague1" target="_blank">[46]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Oprea1" target="_blank">[48]</a>; <i>^m</i>The “fragment-like” library was selected following Verdonk’s criteria <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0090655#pone.0090655-Verdonk1" target="_blank">[50]</a>.</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

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

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

Pie chart showing the distribution by compound type.

<p>Pie chart showing the distribution by compound type.</p

Effects of ixoratannin A-2 and boldine on replication of HIV-1_Δvpu and ARV-resistant HIV-1 strains in CEM-GXR cells.

<p>In all experiments, data are normalized to the replication rate of each HIV-1 strain plus 0.1% DMSO at Day 4. <b>A-B,</b> effects of ixoratannin A-2 (<b>A</b>) and boldine (<b>B</b>) on HIV-1_NL4-3 and HIV-1_Δvpu replication. <b>C-D,</b> effects of ixoratannin A-2 (<b>C</b>) and boldine (<b>D</b>) on replication of ARV-resistant HIV-1 strains.*, p < 0.008 vs. HIV-1_NL4-3 at the same concentration of ixoratannin A-2 or boldine. ǂ, p < 0.008 for strain HIV-1_PR+RT and HIV-1_INT vs. HIV-1_NL4-3 at same concentration of ixoratannin A-2.</p

Effects of compounds on HCV replication.

<p><b>A,</b> Cell viability at 72 h post-infection in the presence of compounds at defined concentrations. Data are normalized to the percent of viable cells in a HCV-infected culture plus 0.1% DMSO. <b>B,</b> HCV replication at 72 h post-infection in the presence of compounds. Data are normalized to percent HCV-infected cells plus 0.1% DMSO.</p

Putative HIV-1 Vpu inhibitors identified from virtual screening of the p-ANAPL.

<p><b>A,</b> Structures of four molecules predicted to interact with the Vpu ion channel [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0121099#pone.0121099.ref020" target="_blank">20</a>]. <b>B,</b> Alignment of four molecules. Chemical substituents that define a shared pharmacophore are highlighted. <b>C,</b> Eight p-ANAPL molecules containing aspects of the shared pharmacophore. For each compound, root mean square deviation (RMSD) values are shown in parentheses.</p