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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

Docked poses of T. b. brucei NH with their cocrystallized ligands (stick figures). (a) IAG-NH with AGV; (b) IG-NH with BTB.
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fig6: Docked poses of T. b. brucei NH with their cocrystallized ligands (stick figures). (a) IAG-NH with AGV; (b) IG-NH with BTB.

Mentions: Figure 6 illustrates the docking poses of the controlled molecules. PDB files of the docked position were generated for control and best compounds using AutoDock Tools [29], which were then imported to LigPlot+ to generate two-dimensional ligand binding interaction plots and superimposed to compare the bindings of different ligands on the same protein and the same ligand on both NH [33]. Our results indicated that the binding pocket of IAG-NH was made of Asp10, Asn12, Lys13, Asp14, Asp15, Asp40, Phe79, Trp83, Thr137, Gly138, Met164, Gly165, Asn173, Glu184, Trp185, Asn186, Leu210, Glu248, Arg252, Asp255, Ala256, Tyr257, Trp260, and Asp261. As for IG-NH, the binding site residues were Asp11, Asp15, Asp16, Asn40, Trp80, Phe83, Leu131, Gly132, Met162, Asn171, Glu177, Phe178, Asn179, Trp205, Phe247, Leu250, Thr254, Thr275, Cys276, Val277, Val278, Pro279, and Asp280.


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

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

Docked poses of T. b. brucei NH with their cocrystallized ligands (stick figures). (a) IAG-NH with AGV; (b) IG-NH with BTB.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Docked poses of T. b. brucei NH with their cocrystallized ligands (stick figures). (a) IAG-NH with AGV; (b) IG-NH with BTB.
Mentions: Figure 6 illustrates the docking poses of the controlled molecules. PDB files of the docked position were generated for control and best compounds using AutoDock Tools [29], which were then imported to LigPlot+ to generate two-dimensional ligand binding interaction plots and superimposed to compare the bindings of different ligands on the same protein and the same ligand on both NH [33]. Our results indicated that the binding pocket of IAG-NH was made of Asp10, Asn12, Lys13, Asp14, Asp15, Asp40, Phe79, Trp83, Thr137, Gly138, Met164, Gly165, Asn173, Glu184, Trp185, Asn186, Leu210, Glu248, Arg252, Asp255, Ala256, Tyr257, Trp260, and Asp261. As for IG-NH, the binding site residues were Asp11, Asp15, Asp16, Asn40, Trp80, Phe83, Leu131, Gly132, Met162, Asn171, Glu177, Phe178, Asn179, Trp205, Phe247, Leu250, Thr254, Thr275, Cys276, Val277, Val278, Pro279, and Asp280.

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