2q5k: Difference between revisions

Revision as of 14:23, 4 May 2008

Crystal structure of lopinavir bound to wild type HIV-1 protease

OverviewOverview

A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2' ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies.

About this StructureAbout this Structure

2Q5K is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.

ReferenceReference

Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres., Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Nathans RS, Schiffer CA, Rana TM, J Med Chem. 2007 Sep 6;50(18):4316-28. Epub 2007 Aug 16. PMID:17696512 Page seeded by OCA on Sun May 4 14:23:54 2008

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OCA

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 [[Image:2q5k.gif|left|200px]]
- {{Structure
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-|GENE= pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1])
+-->
-|DOMAIN=
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-|RELATEDENTRY=[[2q54|2Q54]], [[2q55|2Q55]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2q5k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q5k OCA], [http://www.ebi.ac.uk/pdbsum/2q5k PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2q5k RCSB]</span>
-}}
 '''Crystal structure of lopinavir bound to wild type HIV-1 protease'''
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 [[Category: Nalam, M N.L.]]
 [[Category: Schiffer, C A.]]
-[[Category: drug design]]
+[[Category: Drug design]]
-[[Category: hiv-1 protease]]
+[[Category: Hiv-1 protease]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: protease inhibitor]]
+[[Category: Protease inhibitor]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 14:23:54 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:45:02 2008''