Aliskiren
From Proteopedia
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.[1] Aliskiren is an antagonist to renin.[2] 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.[2] Renin with bound Aliskiren (2v0z). Aliskiren binding site. 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 S3SP region that is equally hydrophobic and hydrophilic and greatly increases binding affinity.[3] Aliskiren interacts with multiple residues in renin. The hydroxyl group hydrogen bonds both aspartate 32 oxygens. The methoxy group in the S3 hydrophobic region hydrogen bonds to secondary amine group of tyrosine 14. The amide group hydrogen bonds with the secondary amine of serine 76.[4] And the terminal amide hydrogen bonds with arginine 74 in the S2' hydrophobic pocket.[5] 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 approved by the Federal Drug Administration (FDA) to treat hypertension. The structure of renin bound with the inhibitor aliskiren has been solved using X-ray diffraction at 3.0 Å resolution.[6] |
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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