Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere.
BACKGROUND
The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and the protease and in the design and optimization of HIV protease inhibitors.


RESULTS
We report here crystal structures at up to 1.7 A resolution of the homodimeric HIV-2 protease in complex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48' and 49' in the flap of the protease and residues 29' and 30' (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor.


CONCLUSIONS
This study shows that besides the residues in the flap and residues 79-81 in the S1 substrate-binding pocket which undergo conformational changes upon inhibitor binding, residues 29 and 30 can also adapt their conformation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.
Tong
L
L
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT 06877, USA.
Pav
S
S
Mui
S
S
Lamarre
D
D
Yoakim
C
C
Beaulieu
P
P
Anderson
P C
PC
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D016333:HIV Protease; D015498:HIV-2 / Q000201:enzymology; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008968:Molecular Conformation; D010875:Pipecolic Acids / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry*; D011487:Protein Conformation
D004151:Dipeptides; D046911:Macromolecular Substances; D010875:Pipecolic Acids; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; D016333:HIV Protease; C065184:p16 protease, Human immunodeficiency virus 2