7faq: Difference between revisions
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==Crystal structure of PDE5A in complex with inhibitor L1== | ==Crystal structure of PDE5A in complex with inhibitor L1== | ||
<StructureSection load='7faq' size='340' side='right'caption='[[7faq]]' scene=''> | <StructureSection load='7faq' size='340' side='right'caption='[[7faq]], [[Resolution|resolution]] 2.20Å' 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=7FAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FAQ FirstGlance]. <br> | <table><tr><td colspan='2'>[[7faq]] is a 1 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=7FAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FAQ FirstGlance]. <br> | ||
</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=7faq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7faq OCA], [https://pdbe.org/7faq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7faq RCSB], [https://www.ebi.ac.uk/pdbsum/7faq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7faq 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]] 2.200136Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2OI:2-[(4-chlorophenyl)methyl]-5-methoxy-3,10-diazatricyclo[6.4.1.0^{4,13}]trideca-1,4(13),5,7-tetraen-9-one'>2OI</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7faq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7faq OCA], [https://pdbe.org/7faq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7faq RCSB], [https://www.ebi.ac.uk/pdbsum/7faq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7faq ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies DeltaG FEP between ligands and their target, which were more consistent with the experimental binding potencies DeltaG EXP (the mean absolute deviations | Delta G FEP - Delta G EXP | < 2 kcal/mol) than those DeltaG MM-PBSA or DeltaG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery. | |||
Free energy perturbation (FEP)-guided scaffold hopping.,Wu D, Zheng X, Liu R, Li Z, Jiang Z, Zhou Q, Huang Y, Wu XN, Zhang C, Huang YY, Luo HB Acta Pharm Sin B. 2022 Mar;12(3):1351-1362. doi: 10.1016/j.apsb.2021.09.027. Epub, 2021 Sep 30. PMID:35530128<ref>PMID:35530128</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7faq" 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: Huang YY]] | [[Category: Huang YY]] | ||
[[Category: Luo HB]] | [[Category: Luo HB]] | ||
[[Category: Wu D]] | [[Category: Wu D]] | ||
Latest revision as of 20:12, 29 November 2023
Crystal structure of PDE5A in complex with inhibitor L1Crystal structure of PDE5A in complex with inhibitor L1
Structural highlights
FunctionPDE5A_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. Publication Abstract from PubMedScaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies DeltaG FEP between ligands and their target, which were more consistent with the experimental binding potencies DeltaG EXP (the mean absolute deviations | Delta G FEP - Delta G EXP | < 2 kcal/mol) than those DeltaG MM-PBSA or DeltaG MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery. Free energy perturbation (FEP)-guided scaffold hopping.,Wu D, Zheng X, Liu R, Li Z, Jiang Z, Zhou Q, Huang Y, Wu XN, Zhang C, Huang YY, Luo HB Acta Pharm Sin B. 2022 Mar;12(3):1351-1362. doi: 10.1016/j.apsb.2021.09.027. Epub, 2021 Sep 30. PMID:35530128[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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