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| | <StructureSection load='6zqz' size='340' side='right'caption='[[6zqz]], [[Resolution|resolution]] 1.88Å' scene=''> | | <StructureSection load='6zqz' size='340' side='right'caption='[[6zqz]], [[Resolution|resolution]] 1.88Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6zqz]] is a 4 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=6ZQZ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZQZ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6zqz]] is a 4 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=6ZQZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZQZ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=QOQ:5-[bis(fluoranyl)methyl]-7-[(3~{S})-1-[(2-chloranyl-6-methyl-pyridin-4-yl)methyl]piperidin-3-yl]-[1,2,4]triazolo[1,5-a]pyrimidine'>QOQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=QOQ:5-[bis(fluoranyl)methyl]-7-[(3~{S})-1-[(2-chloranyl-6-methyl-pyridin-4-yl)methyl]piperidin-3-yl]-[1,2,4]triazolo[1,5-a]pyrimidine'>QOQ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </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=6zqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zqz OCA], [https://pdbe.org/6zqz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zqz RCSB], [https://www.ebi.ac.uk/pdbsum/6zqz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zqz 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=6zqz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zqz OCA], [http://pdbe.org/6zqz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zqz RCSB], [http://www.ebi.ac.uk/pdbsum/6zqz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zqz ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN]] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref> | + | [https://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Leonard, P M]] | + | [[Category: Leonard PM]] |
| - | [[Category: Tresadern, G]] | + | [[Category: Tresadern G]] |
| - | [[Category: Alzheimers disease]]
| + | |
| - | [[Category: Binding free energy]]
| + | |
| - | [[Category: Fep]]
| + | |
| - | [[Category: Free energy perturbation]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Molecular design]]
| + | |
| - | [[Category: Molecular dynamic]]
| + | |
| - | [[Category: Pde2a inhibitor]]
| + | |
| - | [[Category: Phosphodiesterase]]
| + | |
| - | [[Category: Sbdd]]
| + | |
| Structural highlights
Function
PDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[1] [2]
Publication Abstract from PubMed
We describe the hit-to-lead exploration of a [1,2,4]triazolo[1,5-a]pyrimidine phosphodiesterase 2A (PDE2A) inhibitor arising from high-throughput screening. X-ray crystallography enabled structure-guided design, leading to the identification of preferred substructural components. Further rounds of optimization used relative binding free-energy calculations to prioritize different substituents from the large accessible chemical space. The free-energy perturbation (FEP) calculations were performed for 265 putative PDE2A inhibitors, and 100 compounds were synthesized representing a relatively large prospective application providing unexpectedly active molecules with IC50's from 2340 to 0.89 nM. Lead compound 46 originating from the FEP calculations showed PDE2A inhibition IC50 of 1.3 +/- 0.39 nM, approximately 100-fold selectivity versus other PDE enzymes, clean cytochrome P450 profile, in vivo target occupancy, and promise for further lead optimization.
[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration.,Tresadern G, Velter I, Trabanco AA, Van den Keybus F, Macdonald GJ, Somers MVF, Vanhoof G, Leonard PM, Lamers MBAC, Van Roosbroeck YEM, Buijnsters PJJA J Med Chem. 2020 Oct 26. doi: 10.1021/acs.jmedchem.0c01272. PMID:33105987[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
- ↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
- ↑ Tresadern G, Velter I, Trabanco AA, Van den Keybus F, Macdonald GJ, Somers MVF, Vanhoof G, Leonard PM, Lamers MBAC, Van Roosbroeck YEM, Buijnsters PJJA. [1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2A Inhibitors: Structure and Free-Energy Perturbation-Guided Exploration. J Med Chem. 2020 Oct 26. doi: 10.1021/acs.jmedchem.0c01272. PMID:33105987 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01272
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