In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants

Abstract

BackgroundHuman 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.MethodsA 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).ResultsThis 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.ConclusionsThis 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.

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…Some published reports have focused on natural products that are biologically active against one or more protozoan organism or any of their validated drug targets [374][375][376][377][378] while other works have focused on natural products or phytochemicals that were isolated from plants with historical ethnomedicinal therapeutic use [379,380]. Molecular docking has been used to identify, in silico, the selectivity of some compounds or classes of compounds for specific protozoan drug targets.…”

“…coumarin-derived sesquiterpenoid kamalone to be a strongly docking ligand for L. major trypanothione synthase [378]. An in-silico screening study (MolDock) of antiparasitic medicinal plants from West Africa has revealed several phytochemicals with strong, selective docking to a number of Trypanosoma brucei protein targets [379]. This investigation revealed that several triterpenoid and steroid ligands (e.g., grandifoliolenone, lawnermis acid methyl ester, lawsaritol A, wallichianol, 14-hydroxy-isocarpanolide, physagulins J, K, and L, vamonolide, withangulatins E, F, and I, clerosterol, and β-sitosterol, Figure 5) were selective for T. brucei sterol 14α-demethylase.…”

“…This investigation revealed that several triterpenoid and steroid ligands (e.g., grandifoliolenone, lawnermis acid methyl ester, lawsaritol A, wallichianol, 14-hydroxy-isocarpanolide, physagulins J, K, and L, vamonolide, withangulatins E, F, and I, clerosterol, and β-sitosterol, Figure 5) were selective for T. brucei sterol 14α-demethylase. An in-silico screening study (MolDock) of antiparasitic medicinal plants from West Africa has revealed several phytochemicals with strong, selective docking to a number of Trypanosoma brucei protein targets [379]. This investigation revealed that several triterpenoid and steroid ligands (e.g., grandifoliolenone, lawnermis acid methyl ester, lawsaritol A, wallichianol, 14-hydroxy-isocarpanolide, physagulins J, K, and L, vamonolide, withangulatins E, F, and I, clerosterol, and β-sitosterol, Figure 5) were selective for T. brucei sterol 14α-demethylase.…”

“…Several antitrypanosomal phytochemicals have shown strong docking (MolDock) to T. brucei trypanothione reductase, including the iridoid ningpogenin, the diacetylenes 8-hydroxyheptadeca-1-ene-4,6-diyn-3-yl acetate and 8-hydroxyheptadeca-4,6-diyn-3-yl acetate, the flavonoid cissampeloflavone, the anthracenone vismione D, and aculeatin D (Figure 9) [393]. A number of Rauwolfia vomitoria indole alkaloids (ajmalimine, isoajmaline, mitoridine, normitoridine, nortetraphyllicine, and raucaffrinoline, Figure 9) have shown selective docking (MolDock) to this protein target [379]. Numerous phytochemicals have shown antiparasitic activity against T. cruzi [394] and a molecular docking study (MolDock) has revealed several of these to show selective docking to T. cruzi trypanothione reductase [380].…”

Metabolic enzymes of helminth parasites: potential as drug targets

“…This pathway is essential in unicellular parasites from the genus Trypanosoma since they are unable to take up galactose from the environment and rely on "reversing" some of the Leloir pathway reactions in order to generate galactose for glycoprotein synthesis [207][208][209][210][211]. Thus, inhibition of GALE in these species has potential for the development of novel therapeutics [212][213][214][215]. Six inhibitors of F. hepatica UDP-galactose 4-epimerase (EC 5.1.3.2) have been identified; two showed good selectivity over the human enzyme [216].…”