Hydroxyethylamine Isostere of an HIV-1 Protease Inhibitor Prefers Its Amine to the Hydroxy Group in Binding to Catalytic Aspartates. A Synchrotron Study of HIV-1 Protease in Complex with a Peptidomimetic Inhibitor

• Published in: Journal of medicinal chemistry 2002-03, Vol.45 (7), p.1432-1438
• Main Authors: Dohnálek, Jan, Hašek, Jindřich, Dušková, Jarmila, Petroková, Hana, Hradilek, Martin, Souček, Milan, Konvalinka, Jan, Brynda, Jiří, Sedláček, Juraj, Fábry, Milan
• Format: Article
• Language: English
• Subjects: Amines - chemistry; Amino Acids - chemistry; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Aspartic Acid - chemistry; Binding Sites; Biological and medical sciences; Catalysis; Dimerization; Endopeptidases - chemistry; Ethanolamines - chemistry; Glycerol - chemistry; HIV Protease - metabolism; HIV Protease Inhibitors - chemistry; Hydrogen Bonding; Kinetics; Medical sciences; Models, Chemical; Models, Molecular; Oxygen - chemistry; Peptide Fragments; Pharmacology. Drug treatments; Protein Binding; Protein Conformation; Synchrotrons; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010979e

A complex structure of HIV-1 protease with a hydroxyethylamine-containing inhibitor Boc-Phe-Ψ[(S)-CH(OH)CH2NH]-Phe-Gln-Phe-NH2 has been determined by X-ray diffraction to 1.8 Å resolution. The inhibitor is bound in the active site of the protease dimer with its hydroxyethylamine isostere participating in hydrogen bonds to the catalytic aspartates 25 and 25‘ and glycine 27‘ of the active site triads via five hydrogen bonds. The isostere amine interactions with the catalytic aspartates result in a displacement of the isostere hydroxy group in comparison with the common position known for analogous hydroxyethylamine containing inhibitors. A comparison with another inhibitor of this series shows that the change of one atom of the P2‘ side chain (Glu/Gln) leads to an altered ability of creating hydrogen bonds to the active site and within the inhibitor molecule. The diffraction data collected at a synchrotron radiation source enabled a detailed analysis of the complex solvation and of alternative conformations of protein side chains.