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Reflection on design and testing of pancreatic alpha-amylase inhibitors: an in silico comparison between rat and rabbit enzyme models.

Khalil-Moghaddam S, Ebrahim-Habibi A, Pasalar P, Yaghmaei P, Hayati-Roodbari N - Daru (2012)

Bottom Line: In order to find compounds that would be effective amylase inhibitors, in vitro and in vivo models are usually used.The overall result is that rabbit enzyme could probably be a better choice in this regard, but in the case of large ligands, which could make putative interactions with the -4 subsite of pancreatic alpha-amylase, interpretation of results should be made cautiously.In the case of alpha-amylase, three-dimensional structures of animal enzymes show differences with the human one which should be taken into account when testing potential new drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biology Department, Science and Research Branch, Islamic Azad University, Tehran, Iran. yaghmaei_p@srbiau.ac.ir.

ABSTRACT

Background: Inhibitors of pancreatic alpha-amylase are potential drugs to treat diabetes and obesity. In order to find compounds that would be effective amylase inhibitors, in vitro and in vivo models are usually used. The accuracy of models is limited, but these tools are nonetheless valuable. In vitro models could be used in large screenings involving thousands of chemicals that are tested to find potential lead compounds. In vivo models are still used as preliminary mean of testing compounds behavior in the whole organism. In the case of alpha-amylase inhibitors, both rats and rabbits could be chosen as in vivo models. The question was which animal could present more accuracy with regard to its pancreatic alpha-amylase.

Results: As there is no crystal structure of these enzymes, a molecular modeling study was done in order to compare the rabbit and rat enzymes with the human one. The overall result is that rabbit enzyme could probably be a better choice in this regard, but in the case of large ligands, which could make putative interactions with the -4 subsite of pancreatic alpha-amylase, interpretation of results should be made cautiously.

Conclusion: Molecular modeling tools could be used to choose the most suitable model enzyme that would help to identify new enzyme inhibitors. In the case of alpha-amylase, three-dimensional structures of animal enzymes show differences with the human one which should be taken into account when testing potential new drugs.

No MeSH data available.


Related in: MedlinePlus

Results of the potential energy versus time, obtained for a 5000 picoseconds molecular dynamics simulation of human pancreatic amylase containing the seven-ringed ligand.
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Figure 5: Results of the potential energy versus time, obtained for a 5000 picoseconds molecular dynamics simulation of human pancreatic amylase containing the seven-ringed ligand.

Mentions: A short molecular dynamics simulation was then performed to get an insight of the interaction of the ligand with flexible active site residues in an aqueous environment. It should be mentioned that this simulation was ran as an alternative to flexible docking, for 5000 picoseconds which is acceptable in these cases [31,32]. The system potential energy is shown in Figure 5 and is indicative of an equilibrated stage in the last 1000 picoseconds.


Reflection on design and testing of pancreatic alpha-amylase inhibitors: an in silico comparison between rat and rabbit enzyme models.

Khalil-Moghaddam S, Ebrahim-Habibi A, Pasalar P, Yaghmaei P, Hayati-Roodbari N - Daru (2012)

Results of the potential energy versus time, obtained for a 5000 picoseconds molecular dynamics simulation of human pancreatic amylase containing the seven-ringed ligand.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3584935&req=5

Figure 5: Results of the potential energy versus time, obtained for a 5000 picoseconds molecular dynamics simulation of human pancreatic amylase containing the seven-ringed ligand.
Mentions: A short molecular dynamics simulation was then performed to get an insight of the interaction of the ligand with flexible active site residues in an aqueous environment. It should be mentioned that this simulation was ran as an alternative to flexible docking, for 5000 picoseconds which is acceptable in these cases [31,32]. The system potential energy is shown in Figure 5 and is indicative of an equilibrated stage in the last 1000 picoseconds.

Bottom Line: In order to find compounds that would be effective amylase inhibitors, in vitro and in vivo models are usually used.The overall result is that rabbit enzyme could probably be a better choice in this regard, but in the case of large ligands, which could make putative interactions with the -4 subsite of pancreatic alpha-amylase, interpretation of results should be made cautiously.In the case of alpha-amylase, three-dimensional structures of animal enzymes show differences with the human one which should be taken into account when testing potential new drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biology Department, Science and Research Branch, Islamic Azad University, Tehran, Iran. yaghmaei_p@srbiau.ac.ir.

ABSTRACT

Background: Inhibitors of pancreatic alpha-amylase are potential drugs to treat diabetes and obesity. In order to find compounds that would be effective amylase inhibitors, in vitro and in vivo models are usually used. The accuracy of models is limited, but these tools are nonetheless valuable. In vitro models could be used in large screenings involving thousands of chemicals that are tested to find potential lead compounds. In vivo models are still used as preliminary mean of testing compounds behavior in the whole organism. In the case of alpha-amylase inhibitors, both rats and rabbits could be chosen as in vivo models. The question was which animal could present more accuracy with regard to its pancreatic alpha-amylase.

Results: As there is no crystal structure of these enzymes, a molecular modeling study was done in order to compare the rabbit and rat enzymes with the human one. The overall result is that rabbit enzyme could probably be a better choice in this regard, but in the case of large ligands, which could make putative interactions with the -4 subsite of pancreatic alpha-amylase, interpretation of results should be made cautiously.

Conclusion: Molecular modeling tools could be used to choose the most suitable model enzyme that would help to identify new enzyme inhibitors. In the case of alpha-amylase, three-dimensional structures of animal enzymes show differences with the human one which should be taken into account when testing potential new drugs.

No MeSH data available.


Related in: MedlinePlus