In-silico Investigation of Antitrypanosomal Phytochemicals from Nigerian Medicinal Plants

William N Setzer,Ifedayo V Ogungbe,Kiyoshi Kita

doi:10.1371/journal.pntd.0001727

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.

Highlights

Human African trypanosomiasis (HAT), known as sleeping sickness, is caused by the single-celled kinetoplastid parasites, Trypanosoma brucei, which are transmitted to humans by infected tsetse flies (Glossina spp.)
Some of the potential T. brucei drug targets that we considered in this work include adenosine kinase [10], pteridine reductase 1 [11], dihydrofolate reductase [12], trypanothione reductase [13], cathepsin B [14], heat shock protein 90 [15], as well as sterol 14ademethylase (CYP51) [16], nucleoside hydrolase [17], triose phosphate isomerase [18], nucleoside 2-deoxyribosyltransferase [19], UDP-galactose 49 epimerase [20] and ornithine decarboxylase [21]
We have evaluated the interaction of compounds that were isolated from some antitrypanosomal Nigerian medicinal plants (Table S1) against potential protein drug targets in Trypanosoma brucei for which X-ray crystal structures were available from the Protein Data Bank (PDB)

Summary

Introduction

Human African trypanosomiasis (HAT), known as sleeping sickness, is caused by the single-celled kinetoplastid parasites, Trypanosoma brucei, which are transmitted to humans by infected tsetse flies (Glossina spp.). It is worth noting that the number of reported cases of HAT fell in the past decade, and it has been suggested that a possible elimination of the disease might be in sight [4]. This is a very delightful development for this ‘‘neglected’’ tropical disease, and it is our hope that continued research into new and effective chemotherapy against HAT remains an integral part of public health initiatives in endemic communities. Human African trypanosomiasis (HAT), a parasitic protozoal disease, is caused primarily by two subspecies of Trypanosoma brucei. Many affected people live in remote areas with limited access to health services and, rely on traditional herbal medicines for treatment

Objectives

Methods

Results