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2i0a

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{{STRUCTURE_2i0a| PDB=2i0a | SCENE= }}
{{STRUCTURE_2i0a| PDB=2i0a | SCENE= }}
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'''Crystal Structure of KB-19 complexed with wild type HIV-1 protease'''
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===Crystal Structure of KB-19 complexed with wild type HIV-1 protease===
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==Overview==
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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.
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(as it appears on PubMed at http://www.pubmed.gov), where 17149864 is the PubMed ID number.
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{{ABSTRACT_PUBMED_17149864}}
==About this Structure==
==About this Structure==
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[[Category: Hiv-1 protease]]
[[Category: Hiv-1 protease]]
[[Category: Protease inhibitor]]
[[Category: Protease inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 06:55:23 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 14:16:28 2008''

Revision as of 11:16, 29 July 2008

Image:2i0a.png

Template:STRUCTURE 2i0a

Crystal Structure of KB-19 complexed with wild type HIV-1 protease

Template:ABSTRACT PUBMED 17149864

About this Structure

2I0A 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

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