3g72: Difference between revisions
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New page: '''Unreleased structure''' The entry 3g72 is ON HOLD Authors: Bezen on, O., Bur, D., Prade,L., Weller, T., Boss, C., Fischli, W. Description: Design and Preparation of Potent, Non-Pept... |
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==Design and Preparation of Potent, Non-Peptidic, Bioavailable Renin Inhibitors== | |||
<StructureSection load='3g72' size='340' side='right'caption='[[3g72]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3g72]] 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=3G72 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G72 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]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A6T:(1S,5R)-7-{4-[3-(2-CHLORO-3,6-DIFLUOROPHENOXY)PROPYL]PHENYL}-N-CYCLOPROPYL-N-(2,3-DICHLOROBENZYL)-3,9-DIAZABICYCLO[3.3.1]NON-6-ENE-6-CARBOXAMIDE'>A6T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=3g72 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g72 OCA], [https://pdbe.org/3g72 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g72 RCSB], [https://www.ebi.ac.uk/pdbsum/3g72 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g72 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. | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g7/3g72_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3g72 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo. | |||
Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.,Bezencon O, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf O, Grisostomi C, Boss C, Prade L, Delahaye S, Treiber A, Strickner P, Binkert C, Hess P, Steiner B, Fischli W J Med Chem. 2009 Jun 25;52(12):3689-702. PMID:19358611<ref>PMID:19358611</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3g72" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Renin|Renin]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bezencon O]] | |||
[[Category: Boss C]] | |||
[[Category: Bur D]] | |||
[[Category: Fischli W]] | |||
[[Category: Prade L]] | |||
[[Category: Weller T]] | |||
