Aliskiren: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky

@@ Line 2: / Line 2: @@
 Aliskiren (brand names Tekturna and Rasilez) is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension.<ref name="a2">[https://web.archive.org/web/20070322214927/http://www.cbc.ca/cp/HealthScout/070306/6030611AU.html "First Hypertension Drug to Inhibit Kidney Enzyme Approved".] CBC. 2007-03-06. Archived from the original on 2007-03-22. Retrieved 2007-03-14.</ref>
-Aliskiren is an antagonist to renin.<ref name="a12">PMID:10903938</ref> Renin, the first enzyme in the renin–angiotensin–aldosterone system, plays a role in blood pressure control. It cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus blood pressure.<ref name="a12">PMID:10903938</ref>
+Aliskiren is an antagonist to renin.<ref name="a12">PMID:10903938</ref> [[Renin]], the first enzyme in the renin–angiotensin–aldosterone system, plays a role in blood pressure control. It cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus blood pressure.<ref name="a12">PMID:10903938</ref>
-<scene name='Sandbox_Reserved_489/Asymetricunit2v0z/1'>Renin with Bound Aliskiren</scene> ([[2v0z]]).
+<scene name='10/1020133/Cv/3'>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.
+<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 <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.
 Aliskiren is approved by the [http://www.fda.gov/ Federal Drug Administration (FDA)] to treat hypertension.