ction. Based upon the crystal structure of the 4-hydroxy-2-pyrone 111/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 the required pharmacophore (the 4-hydroxy group with hydrogen-bonding interactions with the two catalytic aspartic acid residues and the lactone 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' subsites of the enzyme active site. The crystal structure of a number of representative 5,6-dihydro-4-hydroxy-2-pyrones complexed with the HIV protease were also determined to provide better understanding of the interaction between the enzyme and these inhibitors to aid the structure-based drug design effort.
The crystal structure of the ligands in the enzyme active site did not always agree with the conformations expected from experience with previous pyrone inhibitors. This is like
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