1pro
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(New page: 200px<br /> <applet load="1pro" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pro, resolution 1.8Å" /> '''HIV-1 PROTEASE DIMER...)
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Revision as of 12:17, 8 November 2007
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HIV-1 PROTEASE DIMER COMPLEXED WITH A-98881
Overview
The design, synthesis, and molecular modeling studies of a novel series of, azacyclic ureas, which are inhibitors of human immunodeficiency virus type, 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and, S2' substrate-binding sites of HIV-1 protease are described. The synthesis, of this series is highly flexible in the sense that the P1', P2, and P2', residues of the inhibitors can be changed independently. Molecular, modeling studies on the phenyl ring of the P2 and P2' ligand suggested, incorporation of hydrogen-bonding donor/acceptor groups at the 3' and, 4-positions of the phenyl ring should increase binding potency. This led, to the discovery of compound 7f (A-98881), which possesses high potency in, the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture, assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares, well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.
About this Structure
1PRO is a Single protein structure of sequence from Human immunodeficiency virus 1 with A88 as ligand. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Full crystallographic information is available from OCA.
Reference
A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease., Sham HL, Zhao C, Stewart KD, Betebenner DA, Lin S, Park CH, Kong XP, Rosenbrook W Jr, Herrin T, Madigan D, Vasavanonda S, Lyons N, Molla A, Saldivar A, Marsh KC, McDonald E, Wideburg NE, Denissen JF, Robins T, Kempf DJ, Plattner JJ, Norbeck DW, J Med Chem. 1996 Jan 19;39(2):392-7. PMID:8558507
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