Structural basis for rational design of inhibitors targeting Trypanosoma cruzi Sterol 14α-demethylase: Two regions of the enzyme molecule potentiate its inhibition

Laura Friggeri, Tatiana Y. Hargrove, Girish Rachakonda, Amanda D. Williams, Zdzislaw Wawrzak, Roberto Di Santo, Daniela De Vita, Michael R. Waterman, Silvano Tortorella, Fernando Villalta, Galina I. Lepesheva*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    32 Scopus citations

    Abstract

    Chagas disease, which was once thought to be confined to endemic regions of Latin America, has now gone global, becoming a new worldwide challenge with no cure available. The disease is caused by the protozoan parasite Trypanosoma cruzi, which depends on the production of endogenous sterols, and therefore can be blocked by sterol 14α-demethylase (CYP51) inhibitors. Here we explore the spectral binding parameters, inhibitory effects on T. cruzi CYP51 activity, and antiparasitic potencies of a new set of β-phenyl imidazoles. Comparative structural characterization of the T. cruzi CYP51 complexes with the three most potent inhibitors reveals two opposite binding modes of the compounds ((R)-6, EC50 = 1.2 nM, vs (S)-2/(S)-3, EC50 = 1.0/5.5 nM) and suggests the entrance into the CYP51 substrate access channel and the heme propionate-supporting ceiling of the binding cavity as two distinct areas of the protein that enhance molecular recognition and therefore could be used for the development of more effective antiparasitic drugs.

    Original languageEnglish (US)
    Pages (from-to)6704-6717
    Number of pages14
    JournalJournal of Medicinal Chemistry
    Volume57
    Issue number15
    DOIs
    StatePublished - Aug 14 2014

    ASJC Scopus subject areas

    • Molecular Medicine
    • Drug Discovery

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