5kos: Difference between revisions
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The | ==Discovery of TAK-272: A Novel, Potent and Orally Active Renin In-hibitor== | ||
<StructureSection load='5kos' size='340' side='right' caption='[[5kos]], [[Resolution|resolution]] 2.41Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5kos]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KOS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KOS FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6VS:2-~{TERT}-BUTYL-4-(3-METHOXYPROPYLAMINO)-~{N}-(2-METHYLPROPYL)-~{N}-[(3~{S},5~{R})-5-MORPHOLIN-4-YLCARBONYLPIPERIDIN-3-YL]PYRIMIDINE-5-CARBOXAMIDE'>6VS</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5koq|5koq]], [[5kot|5kot]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Renin Renin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.15 3.4.23.15] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5kos FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kos OCA], [http://pdbe.org/5kos PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kos RCSB], [http://www.ebi.ac.uk/pdbsum/5kos PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kos ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[[http://www.uniprot.org/uniprot/RENI_HUMAN RENI_HUMAN]] Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:[http://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:[http://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 == | |||
[[http://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 aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-yl)carbonylpiper idin-3-yl]-1H-benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials. | |||
Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.,Imaeda Y, Tokuhara H, Fukase Y, Kanagawa R, Kajimoto Y, Kusumoto K, Kondo M, Snell G, Behnke CA, Kuroita T ACS Med Chem Lett. 2016 Sep 12;7(10):933-938. eCollection 2016 Oct 13. PMID:27774132<ref>PMID:27774132</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5kos" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Renin]] | |||
[[Category: Behnke, C A]] | |||
[[Category: Hideyuki, O]] | |||
[[Category: Lane, W]] | |||
[[Category: Okada, K]] | |||
[[Category: Sang, B C]] | |||
[[Category: Snell, G P]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Protein-inhibitor complex]] | |||
