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Impact of Stereochemistry on Ligand Binding: X-ray Crystallographic Analysis of an Epoxide-Based HIV Protease Inhibitor.

ABSTRACT: A new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configuration of the epoxide carbons, has been selected by HIV-PR during crystallization. The structural characterization of the well-ordered pseudopeptide, inserted in the catalytic channel with its epoxide group intact, provides deeper insights into inhibitor binding and HIV-PR stereoselectivity, which aids development of future epoxide-based HIV inhibitors.

SUBMITTER: Benedetti F

PROVIDER: S-EPMC4160752 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Impact of Stereochemistry on Ligand Binding: X-ray Crystallographic Analysis of an Epoxide-Based HIV Protease Inhibitor.

Benedetti Fabio F Berti Federico F Campaner Pietro P Fanfoni Lidia L Demitri Nicola N Olajuyigbe Folasade M FM De March Matteo M Geremia Silvano S

ACS medicinal chemistry letters 20140714 9

A new pseudopeptide epoxide inhibitor, designed for irreversible binding to HIV protease (HIV-PR), has been synthesized and characterized in solution and in the solid state. However, the crystal structure of the complex obtained by inhibitor-enzyme cocrystallization revealed that a minor isomer, with inverted configuration of the epoxide carbons, has been selected by HIV-PR during crystallization. The structural characterization of the well-ordered pseudopeptide, inserted in the catalytic channe ...[more]

PMID: 25221650

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