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. 2012;6(7):e1727.
doi: 10.1371/journal.pntd.0001727. Epub 2012 Jul 24.

In-silico investigation of antitrypanosomal phytochemicals from Nigerian medicinal plants

William N Setzer  1 , Ifedayo V Ogungbe
Affiliations

In-silico investigation of antitrypanosomal phytochemicals from Nigerian medicinal plants

William N Setzer et al. PLoS Negl Trop Dis. 2012.

Abstract

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. The crystal structure of T. brucei sterol 14α-demethylase, TbCYP51 (PDB 3gw9) .
The docked ligand is carapolide A (stick figure). The co-crystallized ligand is shown as a green wire figure and the heme cofactor is shown as a space-filling structure.
Figure 2
Figure 2. The crystal structure of T. brucei pteridine reductase 1, TbPTR1 (PDB 3jq7) .
Top: Lowest-energy docking poses of pseudocolumbamine (green stick figure) and pseudopalmatine (yellow stick figure) in the crystal structure. The NADP+ 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.
Figure 3
Figure 3. The crystal structure of T. brucei adenosine kinase, TbAK (PDB 3otx) .
The docked poses are the biflavonoids GB1 (turquoise), GB1a (magenta), GB2 (yellow), and garciniflavanone (white). The co-crystallized ligand, bis(adenosine)-5′-pentaphosphate, is shown as a green wire figure.
Figure 4
Figure 4. The crystal structure of T. brucei ornithine decarboxylase, TbODC (PDB 1njj) .
The docked poses are the biflavonoids GB1a (magenta), GB2 (yellow), GB3 (green) and kolaflavanone (brown). The co-crystallized ligands are geneticin (green wire figure) and pyridoxylphosphate/d-ornithine (yellow wire figure).
Figure 5
Figure 5. The crystal structure of T. brucei UDP-galactose 4′-epimerase, TbUDPGE (PDB 1gy8) .
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-O-acetylkhayalactone (green stick figure) in the same crystal structure.
Figure 6
Figure 6. The X-ray crystal structure of T. brucei nucleoside hydrolase, Tb NH (PDB 3fz0) .
The lowest energy docking poses of kolanone (green), oruwacin (magenta), and dehydroepoxymethoxygaertneroside (yellow) are shown in the active site.
Figure 7
Figure 7. The crystal structure of T. brucei dihydrofolate reductase, TbDHFR (PDB 3qfx) .
The docked structure is 3-O-acetylkhayalactone (magenta). The co-crystallized ligand, pyrimethamine, is shown as a green wire figure and the NADPH cofactor as a space-filling structure.
Figure 8
Figure 8. The crystal structure of T. brucei triosephosphate isomerase, TbTIM (PDB 1iih) .
The docked structures are the lowest-energy docking poses of the strongly docking M. lucida anthraquinones (2-formyl-3-hydroxyanthaquinone, 2-formylanthraquinone, 2-hydroxy-3-hydroxymethyl-anthraquinone, nordamnacanthal, rubiadin, and soranjidiol) in the active site of the protein.
Figure 9
Figure 9. The crystal structure of T. brucei triosephosphate isomerase, TbTIM (PDB 1iih) .
The lowest-energy docking poses of 6-hydroxydehydroiso-α-lapachone (left) and 4′-hydroxywithasomnine (right) in the active site are shown. Hydrogen-bonding interactions are indicated by blue dashed lines.
Figure 10
Figure 10. The crystal structure of T. brucei pteridine reductase 1 (TbPTR1, PDB 3jq7 [43]).
Left: Lowest-energy docked pose of 1,3,6,8-tetrahydro-2,5-dimethoxyxanthone. Right: Lowest-energy docked pose of (E)-ethyl 4-methoxycinnamate with T. brucei triosephosphate isomerase (TbTIM, PDB 1iih [50]).
Figure 11
Figure 11. Docking poses of umbelliferone.
Left: In the active sites of rhodesain (PDB 2p7u [40]). Right: In the active site of TbCatB (PDB 3hhi [46]).
Figure 12
Figure 12. The crystal structure of T. brucei trypanothione reductase (TbTR, 2wow [45]).
The docked poses are isoplumbagin (left) and lawsone (right) in the proximity of trypanothione.
Figure 13
Figure 13. Left: Isoplumbagin in the active site of rhodesain (PDB 2p86 .
The S⋅⋅⋅C(3) = 3.18 Å. Right: Lowest-energy docked pose of lawsone in the active site of T. brucei cathepsin B (TbCatB, PDB 3hhi ; S⋅⋅⋅C(2) = 3.73 Å).
Figure 14
Figure 14. Lowest-energy docked poses of 6-hydroxydehydroiso-α-lapachone.
Left: With rhodesain (PDB 2p86 [41]). Right: With TbCatB (PDB 3hhi [46]). Note the proximity and orientation of the quinone moiety with the cysteine sulfur atoms in the active sites.
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