STRUCTURE-BASED DESIGN OF HIV PROTEASE INHIBITORS - 5,6-DIHYDRO-4-HYDROXY-2-PYRONES AS EFFECTIVE, NONPEPTIDIC INHIBITORS

Citation
S. Thaisrivongs et al., STRUCTURE-BASED DESIGN OF HIV PROTEASE INHIBITORS - 5,6-DIHYDRO-4-HYDROXY-2-PYRONES AS EFFECTIVE, NONPEPTIDIC INHIBITORS, Journal of medicinal chemistry, 39(23), 1996, pp. 4630-4642
Citations number
46
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
39
Issue
23
Year of publication
1996
Pages
4630 - 4642
Database
ISI
SICI code
0022-2623(1996)39:23<4630:SDOHPI>2.0.ZU;2-Z
Abstract
From a broad screening program, the 4-hydroxycoumarin phenprocoumon (I ) was previously identified as a lead template with HIV protease inhib itory activity. The crystal structure of phenprocoumon/HIV protease co mplex initiated a structure-based design effort that initially identif ied the 4-hydroxy-2-pyrone U-96988 (II) as a first-generation clinical candidate for the potential treatment of HIV infection. Based upon th e crystal structure of the 4-hydroxy-2-pyrone III/HIV protease complex , a series of analogues incorporating a 5,6-dihydro-4-hydroxy-2-pyrone template were studied. It was recognized that in addition to having t he required pharmacophore (the 4-hydroxy group with hydrogen-bonding i nteraction with the two catalytic aspartic acid residues and the lacto ne moiety replacing the ubiquitous water molecule in the active site), these 5,6-dihydro-4-hydroxy-2-pyrones incorporated side chains at the C-6 position that appropriately extended into the S-1' and S-2' subsi tes of the enzyme active site. The crystal structures of a number of r epresentative 5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV p rotease were also determined to provide better understanding of the in teraction between the enzyme and these inhibitors to aid the structure -based drug design effort. The crystal structures of the ligands in th e enzyme active site did not always agree with the conformations expec ted from experience with previous pyrone inhibitors. This is likely du e to the increased flexibility of the dihydropyrone ring. From this st udy, compound XIX exhibited reasonably high enzyme inhibitory activity (K-i = 15 nM) and showed antiviral activity (IC50 = 5 mu M) in the ce ll-culture assay. This result provided a research direction which led to the discovery of active 5,6-dihydro-4-hydroxy-2-pyrones as potentia l agents for the treatment of HIV infection.