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==[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2 Inhibitors==
==[1,2,4]Triazolo[1,5-a]pyrimidine Phosphodiesterase 2 Inhibitors==
<StructureSection load='6znd' size='340' side='right'caption='[[6znd]]' scene=''>
<StructureSection load='6znd' size='340' side='right'caption='[[6znd]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZND OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZND FirstGlance]. <br>
<table><tr><td colspan='2'>[[6znd]] 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=6ZND OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZND FirstGlance]. <br>
</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=6znd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6znd OCA], [http://pdbe.org/6znd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6znd RCSB], [http://www.ebi.ac.uk/pdbsum/6znd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6znd ProSAT]</span></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]] 2.35&#8491;</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=QMZ:[(3~{S})-3-([1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl]-(3,4,5-trimethoxyphenyl)methanone'>QMZ</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=6znd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6znd OCA], [https://pdbe.org/6znd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6znd RCSB], [https://www.ebi.ac.uk/pdbsum/6znd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6znd ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[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;">
== 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<ref>PMID:33105987</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6znd" style="background-color:#fffaf0;"></div>
==See Also==
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Leonard PM]]
[[Category: Leonard PM]]
[[Category: Tresadern G]]
[[Category: Tresadern G]]
Retrieved from "https://proteopedia.org/6znd"