View source for 5koq


==Discovery of TAK-272: A Novel, Potent and Orally Active Renin In-hibitor==
<StructureSection load='5koq' size='340' side='right'caption='[[5koq]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5koq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KOQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KOQ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6VR:2-~{TERT}-BUTYL-4-(FURAN-2-YLMETHYLAMINO)-~{N}-(2-METHYLPROPYL)-~{N}-[(3~{S})-PIPERIDIN-3-YL]PYRIMIDINE-5-CARBOXAMIDE'>6VR</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5koq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5koq OCA], [https://pdbe.org/5koq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5koq RCSB], [https://www.ebi.ac.uk/pdbsum/5koq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5koq ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[https://omim.org/entry/267430 267430]. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).<ref>PMID:16116425</ref>   Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:[https://omim.org/entry/613092 613092]. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.<ref>PMID:19664745</ref> 
== Function ==
[https://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN] Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 ('Leu-in' to 'Leu-out') by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.

Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors.,Imaeda Y, Tawada M, Suzuki S, Tomimoto M, Kondo M, Tarui N, Sanada T, Kanagawa R, Snell G, Behnke CA, Kubo K, Kuroita T Bioorg Med Chem. 2016 Nov 15;24(22):5771-5780. doi: 10.1016/j.bmc.2016.09.030., Epub 2016 Sep 13. PMID:27687967<ref>PMID:27687967</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5koq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Renin|Renin]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Behnke CA]]
[[Category: Hideyuki O]]
[[Category: Lane W]]
[[Category: Okada K]]
[[Category: Sang B-C]]
[[Category: Snell GP]]