Aliskiren
From Proteopedia
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<scene name='10/1020133/Cv/9'>Aliskiren binding site</scene>. Water molecules are shown as red spheres. | <scene name='10/1020133/Cv/9'>Aliskiren binding site</scene>. Water molecules are shown as red spheres. | ||
| - | Aliskiren is a hydrophilic molecule. When bound to renin, aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly aliskiren occupies the S3<sup>SP</sup> 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='10/1020133/Asp32/1'>aspartate 32</scene> oxygens. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='10/1020133/Tyr14/1'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='10/1020133/Ser76/1'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with | + | Aliskiren is a hydrophilic molecule. When bound to renin, aliskiren occupies the S1, S1', S2', and S3 hydrophobic regions of renin. Most importantly aliskiren occupies the S3<sup>SP</sup> 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='10/1020133/Asp32/1'>aspartate 32</scene> oxygens. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of <scene name='10/1020133/Tyr14/1'>tyrosine 14</scene>. The amide group hydrogen bonds with the secondary amine of <scene name='10/1020133/Ser76/1'>serine 76</scene>.<ref>PMID: 20855222</ref> And the terminal amide hydrogen bonds with <scene name='10/1020133/Arg74/1'>arginine 74</scene> in the S2' hydrophobic pocket.<ref>PMID: 21708467</ref> |
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 3<sup>rd</sup> 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 3<sup>rd</sup> 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. | ||
Revision as of 14:15, 20 December 2023
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References
- ↑ "First Hypertension Drug to Inhibit Kidney Enzyme Approved". CBC. 2007-03-06. Archived from the original on 2007-03-22. Retrieved 2007-03-14.
- ↑ 2.0 2.1 Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter MG. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol. 2000 Jul;7(7):493-504. PMID:10903938
- ↑ Webb RL, Schiering N, Sedrani R, Maibaum J. Direct renin inhibitors as a new therapy for hypertension. J Med Chem. 2010 Nov 11;53(21):7490-520. PMID:20731374 doi:10.1021/jm901885s
- ↑ Politi A, Durdagi S, Moutevelis-Minakakis P, Kokotos G, Mavromoustakos T. Development of accurate binding affinity predictions of novel renin inhibitors through molecular docking studies. J Mol Graph Model. 2010 Nov;29(3):425-35. Epub 2010 Aug 27. PMID:20855222 doi:10.1016/j.jmgm.2010.08.003
- ↑ Wu Y, Shi C, Sun X, Wu X, Sun H. Synthesis, biological evaluation and docking studies of octane-carboxamide based renin inhibitors with extended segments toward S3' site of renin. Bioorg Med Chem. 2011 Jul 15;19(14):4238-49. Epub 2011 Jun 1. PMID:21708467 doi:10.1016/j.bmc.2011.05.059
- ↑ Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen NC, Stutz S, Cumin F, Fuhrer W, Wood JM, Grutter MG. Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chem Biol. 2000 Jul;7(7):493-504. PMID:10903938
