2i0d
From Proteopedia
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|PDB= 2i0d |SIZE=350|CAPTION= <scene name='initialview01'>2i0d</scene>, resolution 1.95Å | |PDB= 2i0d |SIZE=350|CAPTION= <scene name='initialview01'>2i0d</scene>, resolution 1.95Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MUT:(5S)-3-(3-ACETYLPHENYL)-N-[(1S,2R)-1-BENZYL-2-HYDROXY-3-{ISOBUTYL[(4-METHOXYPHENYL)SULFONYL]AMINO}PROPYL]-2-OXO-1,3-OXAZOLIDINE-5-CARBOXAMIDE'>MUT</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | |GENE= pol ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11676 Human immunodeficiency virus 1]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2ioa|2IOA]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2i0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i0d OCA], [http://www.ebi.ac.uk/pdbsum/2i0d PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2i0d RCSB]</span> | ||
}} | }} | ||
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[[Category: Reddy, K K.]] | [[Category: Reddy, K K.]] | ||
[[Category: Schiffer, C A.]] | [[Category: Schiffer, C A.]] | ||
| - | [[Category: ACT]] | ||
| - | [[Category: MUT]] | ||
| - | [[Category: PO4]] | ||
[[Category: drug design]] | [[Category: drug design]] | ||
[[Category: hiv-1 protease]] | [[Category: hiv-1 protease]] | ||
[[Category: protease inhibitor]] | [[Category: protease inhibitor]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:37:58 2008'' |
Revision as of 00:37, 31 March 2008
| |||||||
| , resolution 1.95Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , | ||||||
| Gene: | pol (Human immunodeficiency virus 1) | ||||||
| Related: | 2IOA
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of AD-81 complexed with wild type HIV-1 protease
Overview
Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2' phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with K(i) values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2' phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1' with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor - enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogenbond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (K(i) = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar K(i), which is highly comparable with the best FDA-approved protease inhibitors.
About this Structure
2I0D is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands., Ali A, Reddy GS, Cao H, Anjum SG, Nalam MN, Schiffer CA, Rana TM, J Med Chem. 2006 Dec 14;49(25):7342-56. PMID:17149864
Page seeded by OCA on Mon Mar 31 03:37:58 2008
