6upj | pdb_00006upj

HIV-2 PROTEASE/U99294 COMPLEX

spinqualitylabelsall models 6upj, resolution 2.34Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6upj is a 2 chain structure with sequence from Human immunodeficiency virus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NIU Activity: HIV-1 retropepsin, with EC number 3.4.23.16 Resources: FirstGlance, OCA, RCSB, PDBsum Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps). Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors.,Romines KR, Watenpaugh KD, Tomich PK, Howe WJ, Morris JK, Lovasz KD, Mulichak AM, Finzel BC, Lynn JC, Horng MM, et al. J Med Chem. 1995 May 26;38(11):1884-91. PMID:7783120 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Virus protease

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