2q55
Crystal structure of KK44 bound to HIV-1 protease
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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
2Q55 is a Single protein structure of sequence from Human immunodeficiency virus 1 with and as ligands. 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
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