2i0d
From Proteopedia
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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 with , and as ligands. 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 Fri Feb 15 17:34:31 2008
