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Escherichia coli β-Galactosidase Inhibitors through Modifications at the Aglyconic Moiety: Experimental Evidence of Conformational Distortion in the Molecular Recognition Process

Authors

  • Luis Calle,

    1. Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain), Fax: (+34) 915-360-432
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  • Dr. Virginia Roldós,

    1. Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain), Fax: (+34) 915-360-432
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  • Prof. Dr. F. Javier Cañada,

    1. Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain), Fax: (+34) 915-360-432
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  • María Laura Uhrig,

    1. CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires (Argentina)
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  • Alejandro J. Cagnoni,

    1. CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires (Argentina)
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  • Verónica E. Manzano,

    1. CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires (Argentina)
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  • Oscar Varela,

    1. CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, 1428 Buenos Aires (Argentina)
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  • Prof. Dr. Jesus Jiménez-Barbero

    Corresponding author
    1. Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain), Fax: (+34) 915-360-432
    • Chemical and Physical Biology, Centro de Investigationes Biològicas, CSIC, Ramiro de Maetzu 9, 28040 Madrid (Spain), Fax: (+34) 915-360-432

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Abstract

Herein, we describe the use of thioglycosides as glycosidase inhibitors by employing novel modifications at the reducing end of these glycomimetics. The inhibitors display a basic galactopyranosyl unit (1→4)-bonded to a 3-deoxy-4-thiopentopyranose moiety. The molecular basis of the observed inhibition has been studied by using a combination of NMR spectroscopy and molecular modeling techniques. It is demonstrated that these molecules are not recognized by Escherichia coli β-galactosidase in their ground-state conformation, with a conformational selection process taking place. In fact, the observed conformational distortion depends on the chemical nature of the compounds and results from the rotation around the glycosidic linkage (variation of Φ or Ψ) or from the deformation of the six-membered ring of the pentopyranose. The bound conformations of the ligand are adapted in the enzymatic pocket with a variety of hydrogen-bond, van der Waals, and stacking interactions.

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