Sandbox Reserved 489: Difference between revisions
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There are three generations of renin inhibitors. The first two generation molecules were peptide molecules. These peptide molecules were not specific or effective as renin inhibitors. Aliskiren, part of the 3rd generation, is a nonpeptide renin inhibitor. Small molecule nonpeptide inhibitors such as Aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases. Advancements in crystallography and molecular modeling allowed the discovery of aliskiren. Aliskiren inhibits renin activity. Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure. | There are three generations of renin inhibitors. The first two generation molecules were peptide molecules. These peptide molecules were not specific or effective as renin inhibitors. Aliskiren, part of the 3rd generation, is a nonpeptide renin inhibitor. Small molecule nonpeptide inhibitors such as Aliskiren have good pharmokenetics and are very specific for renin and not other protein peptidases. Advancements in crystallography and molecular modeling allowed the discovery of aliskiren. Aliskiren inhibits renin activity. Since renin is the rate limiting step of the RAS renin inhibition is a successful method to lower blood pressure. | ||
Aliskiren is a hydrophilic molecule. When bound to renin, Aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly Aliskiren occupise the S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity. Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both <scene name='Sandbox_Reserved_489/Asp32/1'>aspartate 32</scene> oxygens. The amine group hydrogen bonds carboxylic acid group of <scene name='Sandbox_Reserved_489/Asp32andgly132/1'>glycine 217 and the oxygen atom of asparate 32</scene>. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='Sandbox_Reserved_489/Tyr14/1'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='Sandbox_Reserved_489/Ser76/2'>serine 76</scene>. And the terminal amide hydrogen bonds with <scene name='Sandbox_Reserved_489/Arg_74/1'>arginine 74</scene> in the S2' hydrophobic pocket. | Aliskiren is a hydrophilic molecule. When bound to renin, Aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly Aliskiren occupise the S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.<ref>PMID: 20731374</ref> Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both <scene name='Sandbox_Reserved_489/Asp32/1'>aspartate 32</scene> oxygens. The amine group hydrogen bonds carboxylic acid group of <scene name='Sandbox_Reserved_489/Asp32andgly132/1'>glycine 217 and the oxygen atom of asparate 32</scene>. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='Sandbox_Reserved_489/Tyr14/1'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='Sandbox_Reserved_489/Ser76/2'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with <scene name='Sandbox_Reserved_489/Arg_74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref> | ||
Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration] to treat hypertension. | Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration] to treat hypertension. | ||
