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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

Scheme of the seven-ring containing ligand containing an acarviostatin derivative and a thiohydantoin-like moiety. Numbering of the rings is arbitrary and has been done in order to facilitate description of its interactions.
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Figure 4: Scheme of the seven-ring containing ligand containing an acarviostatin derivative and a thiohydantoin-like moiety. Numbering of the rings is arbitrary and has been done in order to facilitate description of its interactions.

Mentions: In the next stage, a putative inhibitor was designed to assess the differences of active site ligand binding between the two models. As previously mentioned, acarviostatin-derived products have been reported as potent inhibitors of HPA, and occupancy of seven subsites of HPA active site suggested to be an efficient mean to inhibit the enzyme [28]. On the other hand, acarviosinyl-isomaltosyl-spiro-thiohydantoin has also been previously designed and tested as a potent inhibitor of mammalian amylase [29]. Thus, a hybrid compound structure was designed which contained these two potent moieties. The ligand is composed of a six carbohydrate-based units (as found in the crystal structure 3OLI.pdb), with an added moiety resembling thiohydantoin (Figure 4) in order to be able to fill the seven subsites. Thiohydantoin contains one additional nitrogen atom that was omitted here in order to make a more hydrophobic structure. The compound was manually implemented in the 3OLI.pdb structure by superimposition to the existing ligand. However, a further testing was done with a docking tool (Autodock vina) in order to have an approval for the location of the ligand. The docking method was first assessed with a docking experiment on the crystallized ligand. An RMSD of 1.9 Å was obtained between the best pose obtained by docking and the actual binding mode. This is satisfactory with regard to the less than 2 Å threshold usually used to assess successful docking [30], and especially with regard to the large size and multiple rotatable bonds of the ligand. Results of the proposed compound docking showed that the first docked pose was comparable to the manually positioned ligand, but the latter was further used, since derived from a crystallographically obtained pose.


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)

Scheme of the seven-ring containing ligand containing an acarviostatin derivative and a thiohydantoin-like moiety. Numbering of the rings is arbitrary and has been done in order to facilitate description of its interactions.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Scheme of the seven-ring containing ligand containing an acarviostatin derivative and a thiohydantoin-like moiety. Numbering of the rings is arbitrary and has been done in order to facilitate description of its interactions.
Mentions: In the next stage, a putative inhibitor was designed to assess the differences of active site ligand binding between the two models. As previously mentioned, acarviostatin-derived products have been reported as potent inhibitors of HPA, and occupancy of seven subsites of HPA active site suggested to be an efficient mean to inhibit the enzyme [28]. On the other hand, acarviosinyl-isomaltosyl-spiro-thiohydantoin has also been previously designed and tested as a potent inhibitor of mammalian amylase [29]. Thus, a hybrid compound structure was designed which contained these two potent moieties. The ligand is composed of a six carbohydrate-based units (as found in the crystal structure 3OLI.pdb), with an added moiety resembling thiohydantoin (Figure 4) in order to be able to fill the seven subsites. Thiohydantoin contains one additional nitrogen atom that was omitted here in order to make a more hydrophobic structure. The compound was manually implemented in the 3OLI.pdb structure by superimposition to the existing ligand. However, a further testing was done with a docking tool (Autodock vina) in order to have an approval for the location of the ligand. The docking method was first assessed with a docking experiment on the crystallized ligand. An RMSD of 1.9 Å was obtained between the best pose obtained by docking and the actual binding mode. This is satisfactory with regard to the less than 2 Å threshold usually used to assess successful docking [30], and especially with regard to the large size and multiple rotatable bonds of the ligand. Results of the proposed compound docking showed that the first docked pose was comparable to the manually positioned ligand, but the latter was further used, since derived from a crystallographically obtained pose.

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