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In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors.

Ha CH, Fatima A, Gaurav A - Adv Bioinformatics (2015)

Bottom Line: Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway.Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from -10.23 to -7.14 kcal/mol).These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmaceutical Sciences, UCSI University, 1 Jalan Menara Gading, Taman Connaught, Cheras, 56000 Kuala Lumpur, Malaysia.

ABSTRACT
Human African Trypanosomiasis is endemic to 37 countries of sub-Saharan Africa. It is caused by two related species of Trypanosoma brucei. Current therapies suffer from resistance and public accessibility of expensive medicines. Finding safer and effective therapies of natural origin is being extensively explored worldwide. Pentamidine is the only available therapy for inhibiting the P2 adenosine transporter involved in the purine salvage pathway of the trypanosomatids. The objective of the present study is to use computational studies for the investigation of the probable trypanocidal mechanism of flavonoids. Docking experiments were carried out on eight flavonoids of varying level of hydroxylation, namely, flavone, 5-hydroxyflavone, 7-hydroxyflavone, chrysin, apigenin, kaempferol, fisetin, and quercetin. Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway. Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from -10.23 to -7.14‚ÄČkcal/mol). These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases.

No MeSH data available.


Related in: MedlinePlus

(a) Docked position of (i) apigenin (stick figure) in the binding pocket of IAG-NH and (ii) quercetin (stick figure) in the binding pocket of IG-NH. (b) LigPlot figures of (i) apigenin docked in IAG-NH and (ii) quercetin docked in IG-NH. Amino acid residues forming hydrophobic interactions were highlighted in red circles. Amino acids contributing to hydrogen bonds were labelled green and hydrogen bonds were indicated as dotted lines with bond length labelled in green.
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fig8: (a) Docked position of (i) apigenin (stick figure) in the binding pocket of IAG-NH and (ii) quercetin (stick figure) in the binding pocket of IG-NH. (b) LigPlot figures of (i) apigenin docked in IAG-NH and (ii) quercetin docked in IG-NH. Amino acid residues forming hydrophobic interactions were highlighted in red circles. Amino acids contributing to hydrogen bonds were labelled green and hydrogen bonds were indicated as dotted lines with bond length labelled in green.

Mentions: Overall, all flavonoids showed higher affinity towards IAG-NH than IG-NH. This could be due to the fact that the IAG-NH structure used for docking has a closed and narrower binding pocket compared to that of IG-NH. Thus ligands that are more planar and sufficiently small are able to fit into the IAG-NH pocket. Upon visualizing, the ligands were closer to the amino acid residues in IAG-NH binding pocket; thus the calculated intermolecular forces appeared to be higher. However, this selectivity towards IAG-NH could be further investigated by docking studies with flexible binding pocket or molecular dynamics. Figure 8 shows the docked position of the compounds of the highest binding energy for both enzymes.


In Silico Investigation of Flavonoids as Potential Trypanosomal Nucleoside Hydrolase Inhibitors.

Ha CH, Fatima A, Gaurav A - Adv Bioinformatics (2015)

(a) Docked position of (i) apigenin (stick figure) in the binding pocket of IAG-NH and (ii) quercetin (stick figure) in the binding pocket of IG-NH. (b) LigPlot figures of (i) apigenin docked in IAG-NH and (ii) quercetin docked in IG-NH. Amino acid residues forming hydrophobic interactions were highlighted in red circles. Amino acids contributing to hydrogen bonds were labelled green and hydrogen bonds were indicated as dotted lines with bond length labelled in green.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4660014&req=5

fig8: (a) Docked position of (i) apigenin (stick figure) in the binding pocket of IAG-NH and (ii) quercetin (stick figure) in the binding pocket of IG-NH. (b) LigPlot figures of (i) apigenin docked in IAG-NH and (ii) quercetin docked in IG-NH. Amino acid residues forming hydrophobic interactions were highlighted in red circles. Amino acids contributing to hydrogen bonds were labelled green and hydrogen bonds were indicated as dotted lines with bond length labelled in green.
Mentions: Overall, all flavonoids showed higher affinity towards IAG-NH than IG-NH. This could be due to the fact that the IAG-NH structure used for docking has a closed and narrower binding pocket compared to that of IG-NH. Thus ligands that are more planar and sufficiently small are able to fit into the IAG-NH pocket. Upon visualizing, the ligands were closer to the amino acid residues in IAG-NH binding pocket; thus the calculated intermolecular forces appeared to be higher. However, this selectivity towards IAG-NH could be further investigated by docking studies with flexible binding pocket or molecular dynamics. Figure 8 shows the docked position of the compounds of the highest binding energy for both enzymes.

Bottom Line: Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway.Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from -10.23 to -7.14 kcal/mol).These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases.

View Article: PubMed Central - PubMed

Affiliation: Faculty of Pharmaceutical Sciences, UCSI University, 1 Jalan Menara Gading, Taman Connaught, Cheras, 56000 Kuala Lumpur, Malaysia.

ABSTRACT
Human African Trypanosomiasis is endemic to 37 countries of sub-Saharan Africa. It is caused by two related species of Trypanosoma brucei. Current therapies suffer from resistance and public accessibility of expensive medicines. Finding safer and effective therapies of natural origin is being extensively explored worldwide. Pentamidine is the only available therapy for inhibiting the P2 adenosine transporter involved in the purine salvage pathway of the trypanosomatids. The objective of the present study is to use computational studies for the investigation of the probable trypanocidal mechanism of flavonoids. Docking experiments were carried out on eight flavonoids of varying level of hydroxylation, namely, flavone, 5-hydroxyflavone, 7-hydroxyflavone, chrysin, apigenin, kaempferol, fisetin, and quercetin. Using AutoDock 4.2, these compounds were tested for their affinity towards inosine-adenosine-guanosine nucleoside hydrolase and the inosine-guanosine nucleoside hydrolase, the major enzymes of the purine salvage pathway. Our results showed that all of the eight tested flavonoids showed high affinities for both hydrolases (lowest free binding energy ranging from -10.23 to -7.14‚ÄČkcal/mol). These compounds, especially the hydroxylated derivatives, could be further studied as potential inhibitors of the nucleoside hydrolases.

No MeSH data available.


Related in: MedlinePlus