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2chm

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Revision as of 11:43, 3 February 2021

Crystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in PDE5

Structural highlights

2chm is a 1 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:	1f0j, 1jp1, 1jp2, 1ro6, 1ro9, 1ror, 1rkp, 1t9r, 1t9s, 1tb5, 1tbf, 1udt, 1udu, 1uho, 1xlx, 1xlz, 1xm4, 1xm6, 1xmu, 1xmy, 1xn0, 1xos, 1xot, 1xoz, 1xp0, 1y2h, 1y2j
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PDE5A_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dih ydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability.,Allerton CM, Barber CG, Beaumont KC, Brown DG, Cole SM, Ellis D, Lane CA, Maw GN, Mount NM, Rawson DJ, Robinson CM, Street SD, Summerhill NW J Med Chem. 2006 Jun 15;49(12):3581-94. PMID:16759100^[1]

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

References

↑ Allerton CM, Barber CG, Beaumont KC, Brown DG, Cole SM, Ellis D, Lane CA, Maw GN, Mount NM, Rawson DJ, Robinson CM, Street SD, Summerhill NW. A novel series of potent and selective PDE5 inhibitors with potential for high and dose-independent oral bioavailability. J Med Chem. 2006 Jun 15;49(12):3581-94. PMID:16759100 doi:10.1021/jm060113e

1 Structural highlights
2 Function
3 Evolutionary Conservation
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/2chm"

@@ Line 3: / Line 3: @@
 <StructureSection load='2chm' size='340' side='right'caption='[[2chm]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2chm]] is a 1 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=2CHM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2CHM FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2chm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2CHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CHM FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3P4:5-[2-(BUT-3-EN-1-YLOXY)-5-(1-HYDROXYVINYL)PYRIDIN-3-YL]-3-ETHYL-2-(1-ETHYLAZETIDIN-3-YL)-1,2,6,7A-TETRAHYDRO-7H-PYRAZOLO[4,3-D]PYRIMIDIN-7-ONE'>3P4</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3P4:5-[2-(BUT-3-EN-1-YLOXY)-5-(1-HYDROXYVINYL)PYRIDIN-3-YL]-3-ETHYL-2-(1-ETHYLAZETIDIN-3-YL)-1,2,6,7A-TETRAHYDRO-7H-PYRAZOLO[4,3-D]PYRIMIDIN-7-ONE'>3P4</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1f0j|1f0j]], [[1jp1|1jp1]], [[1jp2|1jp2]], [[1ro6|1ro6]], [[1ro9|1ro9]], [[1ror|1ror]], [[1rkp|1rkp]], [[1t9r|1t9r]], [[1t9s|1t9s]], [[1tb5|1tb5]], [[1tbf|1tbf]], [[1udt|1udt]], [[1udu|1udu]], [[1uho|1uho]], [[1xlx|1xlx]], [[1xlz|1xlz]], [[1xm4|1xm4]], [[1xm6|1xm6]], [[1xmu|1xmu]], [[1xmy|1xmy]], [[1xn0|1xn0]], [[1xos|1xos]], [[1xot|1xot]], [[1xoz|1xoz]], [[1xp0|1xp0]], [[1y2h|1y2h]], [[1y2j|1y2j]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1f0j|1f0j]], [[1jp1|1jp1]], [[1jp2|1jp2]], [[1ro6|1ro6]], [[1ro9|1ro9]], [[1ror|1ror]], [[1rkp|1rkp]], [[1t9r|1t9r]], [[1t9s|1t9s]], [[1tb5|1tb5]], [[1tbf|1tbf]], [[1udt|1udt]], [[1udu|1udu]], [[1uho|1uho]], [[1xlx|1xlx]], [[1xlz|1xlz]], [[1xm4|1xm4]], [[1xm6|1xm6]], [[1xmu|1xmu]], [[1xmy|1xmy]], [[1xn0|1xn0]], [[1xos|1xos]], [[1xot|1xot]], [[1xoz|1xoz]], [[1xp0|1xp0]], [[1y2h|1y2h]], [[1y2j|1y2j]]</div></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=2chm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2chm OCA], [http://pdbe.org/2chm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2chm RCSB], [http://www.ebi.ac.uk/pdbsum/2chm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2chm ProSAT]</span></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=2chm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2chm OCA], [https://pdbe.org/2chm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2chm RCSB], [https://www.ebi.ac.uk/pdbsum/2chm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2chm ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PDE5A_HUMAN PDE5A_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP.
+[[https://www.uniprot.org/uniprot/PDE5A_HUMAN PDE5A_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP.
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 31: / Line 31: @@
 ==See Also==
-*[[Phosphodiesterase|Phosphodiesterase]]
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>

2chm

From Proteopedia

Revision as of 11:43, 3 February 2021

Crystal structure of N2 substituted pyrazolo pyrimidinones - a flipped binding mode in PDE5

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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