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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 kcal/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

The estimated inhibition constant (Ki) from docking results of the compounds with IAG-NH and IG-NH from T. b. brucei.
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fig5: The estimated inhibition constant (Ki) from docking results of the compounds with IAG-NH and IG-NH from T. b. brucei.

Mentions: For all ligands docked, the 50 runs were grouped into a range of 1-2 and 1–8 multimember conformational clusters for IAG-NH and IG-NH, respectively. All docking conformations were visualized using AutoDock Tools 1.5.6 so as to ensure the ligands were docked into the defined pocket. Figure 4 presents the lowest binding energy from the largest cluster chosen to represent the result of each docking, regardless of the cluster rank. This is based on the rationale that conformations in the largest cluster are more statistically possible. The estimated inhibition constant, Ki, calculated at 298.15°K for the selected conformations was recorded as well. The results are presented in Figure 5.


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

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

The estimated inhibition constant (Ki) from docking results of the compounds with IAG-NH and IG-NH from T. b. brucei.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: The estimated inhibition constant (Ki) from docking results of the compounds with IAG-NH and IG-NH from T. b. brucei.
Mentions: For all ligands docked, the 50 runs were grouped into a range of 1-2 and 1–8 multimember conformational clusters for IAG-NH and IG-NH, respectively. All docking conformations were visualized using AutoDock Tools 1.5.6 so as to ensure the ligands were docked into the defined pocket. Figure 4 presents the lowest binding energy from the largest cluster chosen to represent the result of each docking, regardless of the cluster rank. This is based on the rationale that conformations in the largest cluster are more statistically possible. The estimated inhibition constant, Ki, calculated at 298.15°K for the selected conformations was recorded as well. The results are presented in Figure 5.

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 kcal/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