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3upj
From Proteopedia
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HUMAN IMMUNODEFICIENCY VIRUS TYPE 2 PROTEASE MUTANT WITH LYS 57 REPLACED BY LEU (K57L) COMPLEX WITH U096333 [4-HYDROXY-3-[1-(PHENYL)PROPYL]-7-METHOXYCOUMARIN]
Overview
The low oral bioavailability and rapid biliary excretion of, peptide-derived HIV protease inhibitors have limited their utility as, potential therapeutic agents. Our broad screening program to discover, nonpeptidic HIV protease inhibitors had previously identified compound II, (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of, HIV protease complexes containing the peptide-derived inhibitor I, (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3, (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine, N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as, phenprocoumon (compound II), provided a rational basis for the, structure-based design of more active analogues. This investigation, reports on the important finding of a carboxamide functionally, appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone, templates which resulted in a new promising series of nonpeptidic HIV, protease inhibitors with improved enzyme-binding affinity. The most active, diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1, protease with a K(i) value of 0.0014 muM. This research provides a new, design direction for the discovery of more potent HIV protease inhibitors, as potential therapeutic agents for the treatment of HIV infection.
About this Structure
3UPJ is a Single protein structure of sequence from Human immunodeficiency virus 1 with U03 as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors., Thaisrivongs S, Watenpaugh KD, Howe WJ, Tomich PK, Dolak LA, Chong KT, Tomich CC, Tomasselli AG, Turner SR, Strohbach JW, et al., J Med Chem. 1995 Sep 1;38(18):3624-37. PMID:7658450
Page seeded by OCA on Thu Nov 8 14:58:40 2007
