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

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp

Comparative Molecular Docking of Antitrypanosomal Natural Products into Multiple Trypanosoma brucei Drug Targets

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

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp

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

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

In-silico Leishmania Target Selectivity of Antiparasitic Terpenoids

Neglected Tropical Diseases (NTDs), like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs

Carotenoids in Drug Discovery and Medicine: Pathways and Molecular Targets Implicated in Human Diseases

Carotenoids are isoprenoid-derived natural products produced in plants, algae, fungi, and photosynthetic bacteria. Most animals cannot synthesize carotenoids because the biosynthetic machinery to create carotenoids de novo is absent in animals, except arthropods. Carotenoids are biosynthesized from two C20 geranylgeranyl pyrophosphate (GGPP) molecules made from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the methylerythritol 4-phosphate (MEP) route. Carotenoids can be extracted by a variety of methods, including maceration, Soxhlet extraction, supercritical fluid extraction (SFE), microwave-assisted extraction (MAE), accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), pulsed electric field (PEF)-assisted extraction, and enzyme-assisted extraction (EAE). Carotenoids have been reported to exert various biochemical actions, including the inhibition of the Akt/mTOR, Bcl-2, SAPK/JNK, JAK/STAT, MAPK, Nrf2/Keap1, and NF-κB signaling pathways and the ability to increase cholesterol efflux to HDL. Carotenoids are absorbed in the intestine. A handful of carotenoids and carotenoid-based compounds are in clinical trials, while some are currently used as medicines. The application of metabolic engineering techniques for carotenoid production, whole-genome sequencing, and the use of plants as cell factories to produce specialty carotenoids presents a promising future for carotenoid research. In this review, we discussed the biosynthesis and extraction of carotenoids, the roles of carotenoids in human health, the metabolism of carotenoids, and carotenoids as a source of drugs and supplements

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

<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>].

<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.

<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