23 research outputs found

    In-silico investigation of antitrypanosomal phytochemicals from Nigerian medicinal plants.

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    BACKGROUND: Human African trypanosomiasis (HAT), a parasitic protozoal disease, is caused primarily by two subspecies of Trypanosoma brucei. HAT is a re-emerging disease and currently threatens millions of people in sub-Saharan Africa. Many affected people live in remote areas with limited access to health services and, therefore, rely on traditional herbal medicines for treatment. METHODS: A molecular docking study has been carried out on phytochemical agents that have been previously isolated and characterized from Nigerian medicinal plants, either known to be used ethnopharmacologically to treat parasitic infections or known to have in-vitro antitrypanosomal activity. A total of 386 compounds from 19 species of medicinal plants were investigated using in-silico molecular docking with validated Trypanosoma brucei protein targets that were available from the Protein Data Bank (PDB): Adenosine kinase (TbAK), pteridine reductase 1 (TbPTR1), dihydrofolate reductase (TbDHFR), trypanothione reductase (TbTR), cathepsin B (TbCatB), heat shock protein 90 (TbHSP90), sterol 14α-demethylase (TbCYP51), nucleoside hydrolase (TbNH), triose phosphate isomerase (TbTIM), nucleoside 2-deoxyribosyltransferase (TbNDRT), UDP-galactose 4' epimerase (TbUDPGE), and ornithine decarboxylase (TbODC). RESULTS: This study revealed that triterpenoid and steroid ligands were largely selective for sterol 14α-demethylase; anthraquinones, xanthones, and berberine alkaloids docked strongly to pteridine reductase 1 (TbPTR1); chromenes, pyrazole and pyridine alkaloids preferred docking to triose phosphate isomerase (TbTIM); and numerous indole alkaloids showed notable docking energies with UDP-galactose 4' epimerase (TbUDPGE). Polyphenolic compounds such as flavonoid gallates or flavonoid glycosides tended to be promiscuous docking agents, giving strong docking energies with most proteins. CONCLUSIONS: This in-silico molecular docking study has identified potential biomolecular targets of phytochemical components of antitrypanosomal plants and has determined which phytochemical classes and structural manifolds likely target trypanosomal enzymes. The results could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and lead to further phytochemical investigations

    Left: Isoplumbagin in the active site of rhodesain (PDB 2p86 [41].

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    <p>The S⋅⋅⋅C(3) = 3.18 Å. Right: Lowest-energy docked pose of lawsone in the active site of <i>T. brucei</i> cathepsin B (TbCatB, PDB 3hhi <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001727#pntd.0001727-Ogbadoyi1" target="_blank">[46]</a>; S⋅⋅⋅C(2) = 3.73 Å).</p

    The crystal structure of <i>T. brucei</i> UDP-galactose 4<i>′</i>-epimerase, TbUDPGE (PDB 1gy8) [<b>37</b>].

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    <p>Top: Lowest-energy docked poses of garcinal (purple stick figure) and garcinoic acid (yellow stick figure) showing key hydrogen-bonding and hydrophobic interactions. The NAD cofactor is shown as a space-filling structure; hydrogen bonds are depicted as blue dashed lines. Bottom: Lowest-energy docked pose of 3-<i>O</i>-acetylkhayalactone (green stick figure) in the same crystal structure.</p

    Lowest-energy docked poses of 6-hydroxydehydroiso-α-lapachone.

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    <p>Left: With rhodesain (PDB 2p86 <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001727#pntd.0001727-Chaubal1" target="_blank">[41]</a>). Right: With TbCatB (PDB 3hhi <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001727#pntd.0001727-Ogbadoyi1" target="_blank">[46]</a>). Note the proximity and orientation of the quinone moiety with the cysteine sulfur atoms in the active sites.</p

    The crystal structure of <i>T. brucei</i> dihydrofolate reductase, TbDHFR (PDB 3qfx) [<b>44</b>].

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    <p>The docked structure is 3-<i>O</i>-acetylkhayalactone (magenta). The co-crystallized ligand, pyrimethamine, is shown as a green wire figure and the NADPH cofactor as a space-filling structure.</p

    The crystal structure of <i>T. brucei</i> pteridine reductase 1, TbPTR1 (PDB 3jq7) [<b>43</b>].

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    <p>Top: Lowest-energy docking poses of pseudocolumbamine (green stick figure) and pseudopalmatine (yellow stick figure) in the crystal structure. The NADP<sup>+</sup> cofactor is shown as a space-filling structure. Bottom: Lowest-energy docking poses of laxanthone II (brown stick figure) and laxanthone III (dark green stick figure) in the same crystal structure.</p

    The crystal structure of <i>T. brucei</i> adenosine kinase, TbAK (PDB 3otx) [<b>42</b>].

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    <p>The docked poses are the biflavonoids GB1 (turquoise), GB1a (magenta), GB2 (yellow), and garciniflavanone (white). The co-crystallized ligand, <i>bis</i>(adenosine)-5<i>′</i>-pentaphosphate, is shown as a green wire figure.</p

    The crystal structure of <i>T. brucei</i> triosephosphate isomerase, TbTIM (PDB 1iih) [<b>50</b>].

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    <p>The docked structures are the lowest-energy docking poses of the strongly docking <i>M. lucida</i> anthraquinones (2-formyl-3-hydroxyanthaquinone, 2-formylanthraquinone, 2-hydroxy-3-hydroxymethyl-anthraquinone, nordamnacanthal, rubiadin, and soranjidiol) in the active site of the protein.</p

    Docking poses of umbelliferone.

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    <p>Left: In the active sites of rhodesain (PDB 2p7u <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001727#pntd.0001727-Dictionary1" target="_blank">[40]</a>). Right: In the active site of TbCatB (PDB 3hhi <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001727#pntd.0001727-Ogbadoyi1" target="_blank">[46]</a>).</p
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