PMID: 11906284Mar 22, 2002Paper

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

Journal of Medicinal Chemistry
Jan DohnálekMilan Fábry

Abstract

A complex structure of HIV-1 protease with a hydroxyethylamine-containing inhibitor Boc-Phe-Psi[(S)-CH(OH)CH2NH]-Phe-Gln-Phe-NH2 has been determined by X-ray diffraction to 1.8 A 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.

References

Jan 1, 1993·Annual Review of Biochemistry·A Wlodawer, J W Erickson
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Feb 27, 2001·Acta Crystallographica. Section D, Biological Crystallography·J DohnálekM Fábry
Aug 5, 1997·Chemical Reviews·Robert E. Babine, Steven L. Bender
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4

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Citations

May 8, 2009·Organic & Biomolecular Chemistry·Christine PhilippeDanièle Bonnet-Delpon
Nov 25, 2004·European Journal of Biochemistry·Hana PetrokováJindrich Hasek
Apr 7, 2011·The Journal of Physical Chemistry. B·Michal KolárPavel Hobza
Apr 18, 2003·Journal of Medicinal Chemistry·Tereza SkálováJan Konvalinka

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