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5sy3

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Revision as of 11:14, 16 September 2020

Structure-based design of a new series of N-piperidin-3-ylpyrimidine-5-carboxamides as renin inhibitors

Structural highlights

5sy3 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	5sxn, 5sy2, 5sz9
Gene:	REN (HUMAN)
Activity:	Renin, with EC number 3.4.23.15
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 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^[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
↑ Imaeda Y, Tawada M, Suzuki S, Tomimoto M, Kondo M, Tarui N, Sanada T, Kanagawa R, Snell G, Behnke CA, Kubo K, Kuroita T. Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors. Bioorg Med Chem. 2016 Nov 15;24(22):5771-5780. doi: 10.1016/j.bmc.2016.09.030., Epub 2016 Sep 13. PMID:27687967 doi:http://dx.doi.org/10.1016/j.bmc.2016.09.030

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5sy3"

@@ Line 1: / Line 1: @@
 ==Structure-based design of a new series of N-piperidin-3-ylpyrimidine-5-carboxamides as renin inhibitors==
-<StructureSection load='5sy3' size='340' side='right' caption='[[5sy3]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='5sy3' size='340' side='right'caption='[[5sy3]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5sy3]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SY3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5SY3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5sy3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SY3 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5SY3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=74Z:N-[(FURAN-2-YL)METHYL]-5,6,7,8-TETRAHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-4-AMINE'>74Z</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>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=74Z:N-[(FURAN-2-YL)METHYL]-5,6,7,8-TETRAHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-4-AMINE'>74Z</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">[[5sxn|5sxn]], [[5sy2|5sy2]], [[5sz9|5sz9]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">REN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5sy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sy3 OCA], [http://pdbe.org/5sy3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5sy3 RCSB], [http://www.ebi.ac.uk/pdbsum/5sy3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5sy3 ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5sy3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sy3 OCA], [http://pdbe.org/5sy3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5sy3 RCSB], [http://www.ebi.ac.uk/pdbsum/5sy3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5sy3 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 22: / Line 23: @@
 </div>
 <div class="pdbe-citations 5sy3" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Renin|Renin]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Renin]]
 [[Category: Behnke, C A]]

5sy3

From Proteopedia

Revision as of 11:14, 16 September 2020

Structure-based design of a new series of N-piperidin-3-ylpyrimidine-5-carboxamides as renin inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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