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| <scene name='Sandbox_Reserved_489/Asymetricunit2v0z/1'>Renin with Bound Aliskiren</scene> ([[2v0z]]). | | <scene name='Sandbox_Reserved_489/Asymetricunit2v0z/1'>Renin with Bound Aliskiren</scene> ([[2v0z]]). |
| 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. |
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| 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='Sandbox_Reserved_489/Asp32/2'>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/Tyr14/2'>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>
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| Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension. | | Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension. |
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| However, there are certain drug combinations that can be dangerous in combination with aliskiren. The FDA announced on April 20, 2012 that patients with [http://en.wikipedia.org/wiki/Diabetes_mellitus diabetes] should not be prescribed drugs containing aliskiren in combination with [http://en.wikipedia.org/wiki/ACE_inhibitor angiotensin-converting-enzyme (ACE) inhibitors] and [http://en.wikipedia.org/wiki/Angiotensin_II_receptor_antagonist angiotensin receptor blockers (ARBs)]. Examples of drugs that combine aliskiren with other drugs include valturna, tekturna HCT, tekamlo, and amturnide. The drug combinations increase the risk of renal impairment, hypotension, hyperkalemia, and lack of efficacy in diabetes patients. The drug combinations should also be avoided in patients with renal impairments. The announcement was based on a [http://www.novartis.com/ Novartis]-sponsored clinical trial called Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). The FDA also stated that preliminary ALTITUDE data indicated an increase in cardiovascular risks such as stroke and death but further trial results are necessary to confirm these risks.<ref>Lowes, Robert. "Aliskiren in Certain Rx Combos Nixed for Diabetic Patients." ''Webscape Medical News.'' Web MD, 2012. 20 April 2012. <[http://www.medscape.com/viewarticle/762425 http://www.medscape.com/viewarticle/762425]></ref>
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| The structure of renin bound with the inhibitor aliskiren has been solved using X-ray diffraction at 3.0 Å resolution.<ref>PMID: 10903938</ref> | | The structure of renin bound with the inhibitor aliskiren has been solved using X-ray diffraction at 3.0 Å resolution.<ref>PMID: 10903938</ref> |