3sfc: Difference between revisions

Latest revision as of 06:10, 17 October 2024

Structure-Based Optimization of Potent 4- and 6-Azaindole-3-Carboxamides as Renin Inhibitors

Structural highlights

3sfc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:	GOL, NAG, S53
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

RENI_HUMAN Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM: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).^[1] Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:613092. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.^[2]

Function

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.

Publication Abstract from PubMed

The control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system. Starting from a previously disclosed series of potent and nonchiral indole-3-carboxamides, we further explored this motif by structure-based drug design guided by X-ray crystallography in combination with efficient parallel synthesis. This resulted in the discovery of 4- or 6-azaindole derivatives with remarkable potency for renin inhibition. The best compound from these series showed an IC(50) value of 1.3nM.

Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors.,Scheiper B, Matter H, Steinhagen H, Bocskei Z, Fleury V, McCort G Bioorg Med Chem Lett. 2011 Sep 15;21(18):5480-6. Epub 2011 Jul 6. PMID:21840218^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
↑ Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet'al P, Kalbacova M, Baresova V, Sikora J, Blazkova H, Zivny J, Ivanek R, Stranecky V, Sovova J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gubler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug;85(2):204-13. Epub 2009 Aug 6. PMID:19664745 doi:10.1016/j.ajhg.2009.07.010
↑ Scheiper B, Matter H, Steinhagen H, Bocskei Z, Fleury V, McCort G. Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5480-6. Epub 2011 Jul 6. PMID:21840218 doi:10.1016/j.bmcl.2011.06.114

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OCA

[1] Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623

[2] Zivna M, Hulkova H, Matignon M, Hodanova K, Vylet'al P, Kalbacova M, Baresova V, Sikora J, Blazkova H, Zivny J, Ivanek R, Stranecky V, Sovova J, Claes K, Lerut E, Fryns JP, Hart PS, Hart TC, Adams JN, Pawtowski A, Clemessy M, Gasc JM, Gubler MC, Antignac C, Elleder M, Kapp K, Grimbert P, Bleyer AJ, Kmoch S. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure. Am J Hum Genet. 2009 Aug;85(2):204-13. Epub 2009 Aug 6. PMID:19664745 doi:10.1016/j.ajhg.2009.07.010

[3] Scheiper B, Matter H, Steinhagen H, Bocskei Z, Fleury V, McCort G. Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5480-6. Epub 2011 Jul 6. PMID:21840218 doi:10.1016/j.bmcl.2011.06.114

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 3sfc is ON HOLD
+==Structure-Based Optimization of Potent 4- and 6-Azaindole-3-Carboxamides as Renin Inhibitors==
+<StructureSection load='3sfc' size='340' side='right'caption='[[3sfc]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[3sfc]] 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=3SFC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3SFC 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]] 2.1&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=S53:[7-BENZYL-2-(5-FLUORO-2-METHYLPHENOXY)-1-PHENYL-1H-PYRROLO[2,3-C]PYRIDIN-3-YL](PIPERAZIN-1-YL)METHANONE'>S53</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=3sfc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3sfc OCA], [https://pdbe.org/3sfc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3sfc RCSB], [https://www.ebi.ac.uk/pdbsum/3sfc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3sfc 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 control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system. Starting from a previously disclosed series of potent and nonchiral indole-3-carboxamides, we further explored this motif by structure-based drug design guided by X-ray crystallography in combination with efficient parallel synthesis. This resulted in the discovery of 4- or 6-azaindole derivatives with remarkable potency for renin inhibition. The best compound from these series showed an IC(50) value of 1.3nM.
-Authors: Scheiper, B., Matter, H., Steinhagen, H, Bocskei, Z., Fleury, V., McCort, G.
+Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors.,Scheiper B, Matter H, Steinhagen H, Bocskei Z, Fleury V, McCort G Bioorg Med Chem Lett. 2011 Sep 15;21(18):5480-6. Epub 2011 Jul 6. PMID:21840218<ref>PMID:21840218</ref>
-Description: Structure-Based Optimization of Potent 4-and 6-Azaindole-3-Carboxamides as Renin Inhibitors
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 3sfc" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Renin|Renin]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bocskei Z]]
+[[Category: Fleury V]]
+[[Category: Matter H]]
+[[Category: McCort G]]
+[[Category: Scheiper B]]
+[[Category: Steinhagen H]]

3sfc: Difference between revisions

Latest revision as of 06:10, 17 October 2024

Structure-Based Optimization of Potent 4- and 6-Azaindole-3-Carboxamides as Renin Inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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