title: Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors.
abstract: 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.
authors.affiliation: Institute of Cell and Molecular Biology, Uppsala University, Sweden.
authors.forename: Hans O
authors.initials: HO
authors.lastname: Andersson
authors.forename: Kerstin
authors.initials: K
authors.lastname: Fridborg
authors.forename: Seved
authors.initials: S
authors.lastname: Löwgren
authors.forename: Mathias
authors.initials: M
authors.lastname: Alterman
authors.forename: Anna
authors.initials: A
authors.lastname: Mühlman
authors.forename: Magnus
authors.initials: M
authors.lastname: Björsne
authors.forename: Neeraj
authors.initials: N
authors.lastname: Garg
authors.forename: Ingmar
authors.initials: I
authors.lastname: Kvarnström
authors.forename: Wesley
authors.initials: W
authors.lastname: Schaal
authors.forename: Björn
authors.initials: B
authors.lastname: Classon
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielsson
authors.forename: Göran
authors.initials: G
authors.lastname: Ahlsén
authors.forename: Ullrika
authors.initials: U
authors.lastname: Nillroth
authors.forename: Lotta
authors.initials: L
authors.lastname: Vrang
authors.forename: Bo
authors.initials: B
authors.lastname: Oberg
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Torsten
authors.initials: T
authors.lastname: Unge
mesh_terms: 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
chemical_list: D017931:DNA Primers; D017320:HIV Protease Inhibitors; D016333:HIV Protease