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

Setzer WN, Ogungbe IV - PLoS Negl Trop Dis (2012)

Bottom Line: 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).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).The results could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and lead to further phytochemical investigations.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Alabama in Huntsville, Huntsville, Alabama, USA. wsetzer@chemistry.uah.edu

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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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]).
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pntd-0001727-g010: 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]).

Mentions: Cinnamate esters from Securidaca longipedunculata[40] showed selective docking to TbTIM while S. longipedunculata xanthones [40], [93] had a docking preference for TbPTR1. Both of these protein targets have relatively small binding sites, which are more suitable for the small ligands (Fig. 10). The xanthones also docked relatively strongly with TbUDPGE. The S. longipedunculata indole alkaloids dehydroelymoclavine and alkaloid A [94] docked strongly to TbPTR1 and TbAK, respectively, as well as with TbUDPGE (see Table S19).


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

Setzer WN, Ogungbe IV - PLoS Negl Trop Dis (2012)

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]).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404109&req=5

pntd-0001727-g010: 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]).
Mentions: Cinnamate esters from Securidaca longipedunculata[40] showed selective docking to TbTIM while S. longipedunculata xanthones [40], [93] had a docking preference for TbPTR1. Both of these protein targets have relatively small binding sites, which are more suitable for the small ligands (Fig. 10). The xanthones also docked relatively strongly with TbUDPGE. The S. longipedunculata indole alkaloids dehydroelymoclavine and alkaloid A [94] docked strongly to TbPTR1 and TbAK, respectively, as well as with TbUDPGE (see Table S19).

Bottom Line: 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).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).The results could provide the framework for synthetic modification of bioactive phytochemicals, de novo synthesis of structural motifs, and lead to further phytochemical investigations.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, University of Alabama in Huntsville, Huntsville, Alabama, USA. wsetzer@chemistry.uah.edu

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.

Show MeSH
Related in: MedlinePlus