title: 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.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benedetti
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Berti
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campaner
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Fanfoni
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Demitri
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy ; Department of Biochemistry, Federal University of Technology , P.M.B. 704, Akure 340001, Ondo State, Nigeria.
authors.forename: Folasade M
authors.initials: FM
authors.lastname: Olajuyigbe
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: De March
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, Centre of Excellence in Biocrystallography, University of Trieste , Via Giorgeri 1, 34127 Trieste, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Geremia
keywords: Epoxide inhibitor; HIV protease; irreversible inhibition; stereochemistry; structure-based drug design