7zmi
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7zmi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Zika_virus Zika virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZMI FirstGlance]. <br> | <table><tr><td colspan='2'>[[7zmi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Zika_virus Zika virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZMI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZMI FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IXJ:(2~{R})-6-[[(2~{S})-6-azanyl-2-[[(2~{S})-6-azanyl-2-(2-phenylethanoylamino)hexanoyl]amino]hexanoyl]amino]-2-carbamimidamido-hexanoic+acid'>IXJ</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]] 2.15Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IXJ:(2~{R})-6-[[(2~{S})-6-azanyl-2-[[(2~{S})-6-azanyl-2-(2-phenylethanoylamino)hexanoyl]amino]hexanoyl]amino]-2-carbamimidamido-hexanoic+acid'>IXJ</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=7zmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zmi OCA], [https://pdbe.org/7zmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zmi RCSB], [https://www.ebi.ac.uk/pdbsum/7zmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zmi 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=7zmi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zmi OCA], [https://pdbe.org/7zmi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zmi RCSB], [https://www.ebi.ac.uk/pdbsum/7zmi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zmi ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Cyclization of small molecules is a widely applied strategy in drug design for ligand optimization to improve affinity, as it eliminates the putative need for structural preorganization of the ligand before binding, or to improve pharmacokinetic properties. In this work, we provide a deeper insight into the binding thermodynamics of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its linear analogs. Characterization of the thermodynamic binding profiles by isothermal titration calorimetry experiments revealed an unfavorable entropy of the macrocycle compared to the open linear reference ligands. Molecular dynamic simulations and X-ray crystal structure analysis indicated only minor benefits from macrocyclization to fixate a favorable conformation, while linear ligands retained some flexibility even in the protein-bound complex structure, possibly explaining the initially surprising effect of a higher entropic penalty for the macrocyclic ligand. | Cyclization of small molecules is a widely applied strategy in drug design for ligand optimization to improve affinity, as it eliminates the putative need for structural preorganization of the ligand before binding, or to improve pharmacokinetic properties. In this work, we provide a deeper insight into the binding thermodynamics of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its linear analogs. Characterization of the thermodynamic binding profiles by isothermal titration calorimetry experiments revealed an unfavorable entropy of the macrocycle compared to the open linear reference ligands. Molecular dynamic simulations and X-ray crystal structure analysis indicated only minor benefits from macrocyclization to fixate a favorable conformation, while linear ligands retained some flexibility even in the protein-bound complex structure, possibly explaining the initially surprising effect of a higher entropic penalty for the macrocyclic ligand. | ||
| - | Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs.,Hammerschmidt SJ, Huber S, Braun NJ, Lander M, Steinmetzer T, Kersten C Arch Pharm (Weinheim). | + | Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs.,Hammerschmidt SJ, Huber S, Braun NJ, Lander M, Steinmetzer T, Kersten C Arch Pharm (Weinheim). 2023 Apr;356(4):e2200518. doi: 10.1002/ardp.202200518. , Epub 2022 Dec 8. PMID:36480352<ref>PMID:36480352</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 Unlinked NS2B_NS3 Protease from Zika Virus in Complex with Inhibitor MI-2113
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