4mib: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
''' | ==Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)== | ||
<StructureSection load='4mib' size='340' side='right' caption='[[4mib]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mib]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MIB OCA]. <br> | |||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=28M:N-({(3S)-1-[6-TERT-BUTYL-5-METHOXY-8-(2-OXO-1,2-DIHYDROPYRIDIN-3-YL)QUINOLIN-3-YL]PYRROLIDIN-3-YL}METHYL)METHANESULFONAMIDE'>28M</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene><br> | |||
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mia|4mia]], [[4mk7|4mk7]], [[4mk8|4mk8]], [[4mk9|4mk9]], [[4mka|4mka]], [[4mkb|4mkb]]</td></tr> | |||
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr> | |||
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mib OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mib RCSB], [http://www.ebi.ac.uk/pdbsum/4mib PDBsum]</span></td></tr> | |||
<table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
In the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development. | |||
Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]pheny l]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.,Talamas FX, Abbot SC, Anand S, Brameld KA, Carter DS, Chen J, Davis D, de Vicente J, Fung AD, Gong L, Harris SF, Inbar P, Labadie SS, Lee EK, Lemoine R, Le Pogam S, Leveque V, Li J, McIntosh J, Najera I, Park J, Railkar A, Rajyaguru S, Sangi M, Schoenfeld RC, Staben LR, Tan Y, Taygerly JP, Villasenor AG, Weller PE J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s. Epub 2013 Nov 6. PMID:24195700<ref>PMID:24195700</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: RNA-directed RNA polymerase]] | |||
[[Category: Harris, S F.]] | |||
[[Category: Villasenor, A G.]] | |||
[[Category: Ns5b]] | |||
[[Category: Polymerase]] | |||
[[Category: Transferase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 11:15, 7 May 2014
Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)Hepatitis C Virus polymerase NS5B genotype 1b (BK) in complex with Compound 48 (N-({(3S)-1-[6-tert-butyl-5-methoxy-8-(2-oxo-1,2-dihydropyridin-3-yl)quinolin-3-yl]pyrrolidin-3-yl}methyl)methanesulfonamide)
Structural highlights
Publication Abstract from PubMedIn the past few years, there have been many advances in the efforts to cure patients with hepatitis C virus (HCV). The ultimate goal of these efforts is to develop a combination therapy consisting of only direct-antiviral agents (DAAs). In this paper, we discuss our efforts that led to the identification of a bicyclic template with potent activity against the NS5B polymerase, a critical enzyme on the life cycle of HCV. In continuation of our exploration to improve the stilbene series, the 3,5,6,8-tetrasubstituted quinoline core was identified as replacement of the stilbene moiety. 6-Methoxy-2(1H)-pyridone was identified among several heterocyclic headgroups to have the best potency. Solubility of the template was improved by replacing a planar aryl linker with a saturated pyrrolidine. Profiling of the most promising compounds led to the identification of quinoline 41 (RG7109), which was selected for advancement to clinical development. Discovery of N-[4-[6-tert-butyl-5-methoxy-8-(6-methoxy-2-oxo-1H-pyridin-3-yl)-3-quinolyl]pheny l]methanesulfonamide (RG7109), a potent inhibitor of the hepatitis C virus NS5B polymerase.,Talamas FX, Abbot SC, Anand S, Brameld KA, Carter DS, Chen J, Davis D, de Vicente J, Fung AD, Gong L, Harris SF, Inbar P, Labadie SS, Lee EK, Lemoine R, Le Pogam S, Leveque V, Li J, McIntosh J, Najera I, Park J, Railkar A, Rajyaguru S, Sangi M, Schoenfeld RC, Staben LR, Tan Y, Taygerly JP, Villasenor AG, Weller PE J Med Chem. 2014 Mar 13;57(5):1914-31. doi: 10.1021/jm401329s. Epub 2013 Nov 6. PMID:24195700[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||