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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

Interactions of the seven-ringed ligand with subsite −4 of the three pancreatic enzymes. Colour codes of amino acids are as follows: basic residues in pink with blue border, acidic residues in pink with red border, polar residues in pink, hydrophobic (greasy) residues in green. a. Interactions obtained with the ligand after 5000 picoseconds of simulation. The water network seems to be of importance in the interactions between ring number 1 and subsite −4 of the human enzyme. b. Residues found in the vicinity (5Å) of the seven-ringed ligand in human pancreatic enzyme. c. Superimposition of the interacting residues found in human enzyme, with the ones of rabbit and rat enzymes. Residues shown in black are different with the human enzyme in the rabbit and rat models.
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Figure 7: Interactions of the seven-ringed ligand with subsite −4 of the three pancreatic enzymes. Colour codes of amino acids are as follows: basic residues in pink with blue border, acidic residues in pink with red border, polar residues in pink, hydrophobic (greasy) residues in green. a. Interactions obtained with the ligand after 5000 picoseconds of simulation. The water network seems to be of importance in the interactions between ring number 1 and subsite −4 of the human enzyme. b. Residues found in the vicinity (5Å) of the seven-ringed ligand in human pancreatic enzyme. c. Superimposition of the interacting residues found in human enzyme, with the ones of rabbit and rat enzymes. Residues shown in black are different with the human enzyme in the rabbit and rat models.

Mentions: In the case of our ligand, the interactions that occur in the final frame of the simulation are shown in Figure 7a. Residues related to subsite −4 that surround ring 1 of the ligand (see Figure 4) include I51, Q63, G104, A106, V107 and G164 (shown in Figure 7b) and seem to make a hydrophobic pocket. The hydrogen bond that occurs between Q63 and the ligand, as well as the interaction with T163 are also of interest. In order to compare the corresponding residues of RABPA and RPA enzymes related to the subsite −4, a superimposition of the most important residues was done (Figure 7c).


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)

Interactions of the seven-ringed ligand with subsite −4 of the three pancreatic enzymes. Colour codes of amino acids are as follows: basic residues in pink with blue border, acidic residues in pink with red border, polar residues in pink, hydrophobic (greasy) residues in green. a. Interactions obtained with the ligand after 5000 picoseconds of simulation. The water network seems to be of importance in the interactions between ring number 1 and subsite −4 of the human enzyme. b. Residues found in the vicinity (5Å) of the seven-ringed ligand in human pancreatic enzyme. c. Superimposition of the interacting residues found in human enzyme, with the ones of rabbit and rat enzymes. Residues shown in black are different with the human enzyme in the rabbit and rat models.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Interactions of the seven-ringed ligand with subsite −4 of the three pancreatic enzymes. Colour codes of amino acids are as follows: basic residues in pink with blue border, acidic residues in pink with red border, polar residues in pink, hydrophobic (greasy) residues in green. a. Interactions obtained with the ligand after 5000 picoseconds of simulation. The water network seems to be of importance in the interactions between ring number 1 and subsite −4 of the human enzyme. b. Residues found in the vicinity (5Å) of the seven-ringed ligand in human pancreatic enzyme. c. Superimposition of the interacting residues found in human enzyme, with the ones of rabbit and rat enzymes. Residues shown in black are different with the human enzyme in the rabbit and rat models.
Mentions: In the case of our ligand, the interactions that occur in the final frame of the simulation are shown in Figure 7a. Residues related to subsite −4 that surround ring 1 of the ligand (see Figure 4) include I51, Q63, G104, A106, V107 and G164 (shown in Figure 7b) and seem to make a hydrophobic pocket. The hydrogen bond that occurs between Q63 and the ligand, as well as the interaction with T163 are also of interest. In order to compare the corresponding residues of RABPA and RPA enzymes related to the subsite −4, a superimposition of the most important residues was done (Figure 7c).

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