8i71
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8i71]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_B_virus_subtype_adyw Hepatitis B virus subtype adyw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8I71 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8I71 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8i71]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_B_virus_subtype_adyw Hepatitis B virus subtype adyw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8I71 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8I71 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=OTI:3-[(8~{a}~{S})-7-[[5-ethoxycarbonyl-4-(3-fluoranyl-2-methyl-phenyl)-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-3-oxidanylidene-5,6,8,8~{a}-tetrahydro-1~{H}-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic+acid'>OTI</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]] 1.6Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene>, <scene name='pdbligand=OTI:3-[(8~{a}~{S})-7-[[5-ethoxycarbonyl-4-(3-fluoranyl-2-methyl-phenyl)-2-(1,3-thiazol-2-yl)-1,4-dihydropyrimidin-6-yl]methyl]-3-oxidanylidene-5,6,8,8~{a}-tetrahydro-1~{H}-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic+acid'>OTI</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=8i71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8i71 OCA], [https://pdbe.org/8i71 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8i71 RCSB], [https://www.ebi.ac.uk/pdbsum/8i71 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8i71 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=8i71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8i71 OCA], [https://pdbe.org/8i71 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8i71 RCSB], [https://www.ebi.ac.uk/pdbsum/8i71 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8i71 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients. | Described herein is the first-time disclosure of Linvencorvir (RG7907), a clinical compound and a hepatitis B virus (HBV) core protein allosteric modulator, for the treatment of chronic HBV infection. Built upon the core structure of hetero aryl dihydropyrimidine, RG7907 was rationally designed by combining all the drug-like features of low CYP3A4 induction, potent anti-HBV activity, high metabolic stability, low hERG liability, and favorable animal pharmacokinetic (PK) profiles. In particular, the chemistry strategy to mitigate CYP3A4 induction through introducing a large, rigid, and polar substituent at the position that has less interaction with the therapeutic biological target (HBV core proteins herein) is of general interest to the medicinal chemistry community. RG7907 demonstrated favorable animal PK, pharmacodynamics, and safety profiles with sufficient safety margins supporting its clinical development in healthy volunteers and HBV-infected patients. | ||
| - | Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection.,Zhang W, Guo L, Liu H, Wu G, Shi H, Zhou M, Zhang Z, Kou B, Hu T, Zhou Z, Xu Z, Zhou X, Zhou Y, Tian X, Yang G, Young JAT, Qiu H, Ottaviani G, Xie J, Mayweg AV, Shen HC, Zhu W J Med Chem. 2023 Mar | + | Discovery of Linvencorvir (RG7907), a Hepatitis B Virus Core Protein Allosteric Modulator, for the Treatment of Chronic HBV Infection.,Zhang W, Guo L, Liu H, Wu G, Shi H, Zhou M, Zhang Z, Kou B, Hu T, Zhou Z, Xu Z, Zhou X, Zhou Y, Tian X, Yang G, Young JAT, Qiu H, Ottaviani G, Xie J, Mayweg AV, Shen HC, Zhu W J Med Chem. 2023 Mar 23;66(6):4253-4270. doi: 10.1021/acs.jmedchem.3c00173. Epub , 2023 Mar 10. PMID:36896968<ref>PMID:36896968</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
Hepatitis B virus core protein Y132A mutant in complex with Linvencorvir (RG7907), a Hepatitis B Virus (HBV) Core Protein Allosteric Modulator (CpAM)
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