View source for 9c9v


==HBV capsid with compound 3i==
<StructureSection load='9c9v' size='340' side='right'caption='[[9c9v]], [[Resolution|resolution]] 2.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9c9v]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Hepatitis_B_virus Hepatitis B virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9C9V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9C9V FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.63&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1AVK:3-(3-chloranyl-4-fluoranyl-phenyl)-1-(2-methylpropyl)-1-[(1~{R})-1-(1-oxidanylidene-2~{H}-isoquinolin-4-yl)ethyl]urea'>A1AVK</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=9c9v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9c9v OCA], [https://pdbe.org/9c9v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9c9v RCSB], [https://www.ebi.ac.uk/pdbsum/9c9v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9c9v ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/L7R9I1_HBV L7R9I1_HBV] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues. Key analogs demonstrated excellent primary potency, absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic properties, and efficacy in a mouse model of HBV. The optimized lead also displayed potent inhibition of capsid uncoating in HBV-infected HepG2 cells expressing the sodium-taurocholate cotransporting polypeptide (NTCP) receptor, affecting the generation of HBsAg and cccDNA establishment. Based on these results, isoquinolinone derivative AB-836 was advanced into clinical development. In Phase 1b trials, AB-836 demonstrated &gt;3 log(10) reduction in serum HBV DNA, however, further development was discontinued due to the observation of incidental alanine aminotransferase (ALT) elevations.

Rational Design, Synthesis, and Structure-Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836.,Cole AG, Kultgen SG, Mani N, Fan KY, Ardzinski A, Stever K, Dorsey BD, Mesaros EF, Thi EP, Graves I, Tang S, Harasym TO, Lee ACH, Olland A, Suto RK, Sofia MJ J Med Chem. 2024 Sep 4. doi: 10.1021/acs.jmedchem.4c01568. PMID:39231272<ref>PMID:39231272</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9c9v" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Hepatitis B virus]]
[[Category: Large Structures]]
[[Category: Colussi T]]
[[Category: Fontano E]]
[[Category: Olland AM]]
[[Category: Suto RK]]