8cnh
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8cnh]] 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=8CNH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CNH FirstGlance]. <br> | <table><tr><td colspan='2'>[[8cnh]] 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=8CNH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CNH FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V6U:methyl+2-[[3-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-1-methyl-pyrazol-4-yl]methyl]benzoate'>V6U</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]] 2Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V6U:methyl+2-[[3-(2-azanyl-6-chloranyl-pyrimidin-4-yl)-1-methyl-pyrazol-4-yl]methyl]benzoate'>V6U</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=8cnh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cnh OCA], [https://pdbe.org/8cnh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cnh RCSB], [https://www.ebi.ac.uk/pdbsum/8cnh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cnh 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=8cnh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cnh OCA], [https://pdbe.org/8cnh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cnh RCSB], [https://www.ebi.ac.uk/pdbsum/8cnh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cnh ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation. | Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation. | ||
| - | Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.,Sun S, Fushimi M, Rossetti T, Kaur N, Ferreira J, Miller M, Quast J, van den Heuvel J, Steegborn C, Levin LR, Buck J, Myers RW, Kargman S, Liverton N, Meinke PT, Huggins DJ J Chem Inf Model. 2023 | + | Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.,Sun S, Fushimi M, Rossetti T, Kaur N, Ferreira J, Miller M, Quast J, van den Heuvel J, Steegborn C, Levin LR, Buck J, Myers RW, Kargman S, Liverton N, Meinke PT, Huggins DJ J Chem Inf Model. 2023 May 8;63(9):2828-2841. doi: 10.1021/acs.jcim.2c01577. Epub , 2023 Apr 15. PMID:37060320<ref>PMID:37060320</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Crystal structure of human soluble adenylyl cyclase (sAC) in complex with inhibitor TDI-10512
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