4djp: Difference between revisions
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[[ | ==Crystal Structure of wild-type HIV-1 Protease in Complex with MKP73== | ||
<StructureSection load='4djp' size='340' side='right' caption='[[4djp]], [[Resolution|resolution]] 1.40Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4djp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DJP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DJP FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=M73:METHYL+(2S)-3-({[(2S,3R)-3-HYDROXY-4-{[(4-METHOXYPHENYL)SULFONYL][(2S)-2-METHYLBUTYL]AMINO}-1-PHENYLBUTAN-2-YL]CARBAMOYL}OXY)-2-METHYLPROPANOATE'>M73</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4djo|4djo]], [[4djq|4djq]], [[4djr|4djr]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">gag-pol, pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4djp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4djp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4djp RCSB], [http://www.ebi.ac.uk/pdbsum/4djp PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K(i) values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies. | |||
Design, Synthesis, and Biological and Structural Evaluations of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance.,Parai MK, Huggins DJ, Cao H, Nalam MN, Ali A, Schiffer CA, Tidor B, Rana TM J Med Chem. 2012 Jul 26;55(14):6328-41. Epub 2012 Jul 13. PMID:22708897<ref>PMID:22708897</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
< | |||
[[Category: Human immunodeficiency virus 1]] | [[Category: Human immunodeficiency virus 1]] | ||
[[Category: Nalam, M N.L | [[Category: Nalam, M N.L]] | ||
[[Category: Schiffer, C A | [[Category: Schiffer, C A]] | ||
[[Category: Aid]] | [[Category: Aid]] | ||
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
Revision as of 17:25, 9 December 2014
Crystal Structure of wild-type HIV-1 Protease in Complex with MKP73Crystal Structure of wild-type HIV-1 Protease in Complex with MKP73
Structural highlights
Publication Abstract from PubMedA series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K(i) values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies. Design, Synthesis, and Biological and Structural Evaluations of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance.,Parai MK, Huggins DJ, Cao H, Nalam MN, Ali A, Schiffer CA, Tidor B, Rana TM J Med Chem. 2012 Jul 26;55(14):6328-41. Epub 2012 Jul 13. PMID:22708897[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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