Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors.
HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 A resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the delta-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
Andersson
Hans O
HO
Institute of Cell and Molecular Biology, Uppsala University, Sweden.
Fridborg
Kerstin
K
Löwgren
Seved
S
Alterman
Mathias
M
Mühlman
Anna
A
Björsne
Magnus
M
Garg
Neeraj
N
Kvarnström
Ingmar
I
Schaal
Wesley
W
Classon
Björn
B
Karlén
Anders
A
Danielsson
U Helena
UH
Ahlsén
Göran
G
Nillroth
Ullrika
U
Vrang
Lotta
L
Oberg
Bo
B
Samuelsson
Bertil
B
Hallberg
Anders
A
Unge
Torsten
T
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D017931:DNA Primers; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D007700:Kinetics; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D017931:DNA Primers; D017320:HIV Protease Inhibitors; D016333:HIV Protease