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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

Acarviostatin AIV03-derivated ligand interactions within the human enzyme in the 3OLI.pdb files. Interaction diagrams were drawn with the use of MOE.2009.10 ligand-interaction module. Water molecules of the 3OLI.pdb structures have been preserved (6.a) or deleted (6.b) in order to assess their potential significance in ligand-protein interactions. Water molecules that are in the vicinity of amino acids are as HOH 586 (E233, catalytic residue), HOH 791 (N105),HOH 817 (I235) and HOH 832 (A307). Interaction between residues and ligand moieties are hydrogen bonds (indicated by arrows, green arrows indicate side chain donors and acceptors and blue arrows indicate backbone donors and acceptors). 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.
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Figure 6: Acarviostatin AIV03-derivated ligand interactions within the human enzyme in the 3OLI.pdb files. Interaction diagrams were drawn with the use of MOE.2009.10 ligand-interaction module. Water molecules of the 3OLI.pdb structures have been preserved (6.a) or deleted (6.b) in order to assess their potential significance in ligand-protein interactions. Water molecules that are in the vicinity of amino acids are as HOH 586 (E233, catalytic residue), HOH 791 (N105),HOH 817 (I235) and HOH 832 (A307). Interaction between residues and ligand moieties are hydrogen bonds (indicated by arrows, green arrows indicate side chain donors and acceptors and blue arrows indicate backbone donors and acceptors). 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.

Mentions: The seven active cleft subsites occupied by the original ligands span from the −4 subsite to the +3 one. Based on in vitro inhibition studies on acarviostatin derivatives, the −4 subsite has been particularly highlighted as a location whose occupation would increase the potency of designed inhibitors [18]. It is interesting to note that interaction of the original ligand with both −4 and +3 subsites occurs mainly through water molecules. Figure 6 shows an interaction diagram obtained with MOE.2009.10 when the solvent molecules of the 3OLI.pdb file were present or absent. As observed in Figure 6a, interaction of the ligand with subsite −4 N105 and D147 occurs via water molecules. Similarly, subsite +3 interactions are also happening via water molecule (in this structure). When water molecules are deleted, and the interaction diagram redrawn (Figure 6b), the two ending moieties of the ligand show no particular interactions.


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)

Acarviostatin AIV03-derivated ligand interactions within the human enzyme in the 3OLI.pdb files. Interaction diagrams were drawn with the use of MOE.2009.10 ligand-interaction module. Water molecules of the 3OLI.pdb structures have been preserved (6.a) or deleted (6.b) in order to assess their potential significance in ligand-protein interactions. Water molecules that are in the vicinity of amino acids are as HOH 586 (E233, catalytic residue), HOH 791 (N105),HOH 817 (I235) and HOH 832 (A307). Interaction between residues and ligand moieties are hydrogen bonds (indicated by arrows, green arrows indicate side chain donors and acceptors and blue arrows indicate backbone donors and acceptors). 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Acarviostatin AIV03-derivated ligand interactions within the human enzyme in the 3OLI.pdb files. Interaction diagrams were drawn with the use of MOE.2009.10 ligand-interaction module. Water molecules of the 3OLI.pdb structures have been preserved (6.a) or deleted (6.b) in order to assess their potential significance in ligand-protein interactions. Water molecules that are in the vicinity of amino acids are as HOH 586 (E233, catalytic residue), HOH 791 (N105),HOH 817 (I235) and HOH 832 (A307). Interaction between residues and ligand moieties are hydrogen bonds (indicated by arrows, green arrows indicate side chain donors and acceptors and blue arrows indicate backbone donors and acceptors). 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.
Mentions: The seven active cleft subsites occupied by the original ligands span from the −4 subsite to the +3 one. Based on in vitro inhibition studies on acarviostatin derivatives, the −4 subsite has been particularly highlighted as a location whose occupation would increase the potency of designed inhibitors [18]. It is interesting to note that interaction of the original ligand with both −4 and +3 subsites occurs mainly through water molecules. Figure 6 shows an interaction diagram obtained with MOE.2009.10 when the solvent molecules of the 3OLI.pdb file were present or absent. As observed in Figure 6a, interaction of the ligand with subsite −4 N105 and D147 occurs via water molecules. Similarly, subsite +3 interactions are also happening via water molecule (in this structure). When water molecules are deleted, and the interaction diagram redrawn (Figure 6b), the two ending moieties of the ligand show no particular interactions.

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