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    Bioorg Med Chem Lett. 2006 Oct 1;16(19):5084-7. Epub 2006 Aug 2.

    The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme.

    Source

    MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.

    Abstract

    Enzyme-inhibitor recognition is considered one of the most fundamental aspects in the area of drug discovery. However, the molecular mechanism of this recognition process (induced fit or prebinding and adaptive selection among multiple conformers) in several cases remains unexplored. In order to shed light toward this step of the recognition process in the case of human angiotensin I converting enzyme (hACE) and its inhibitor captopril, we have established a novel combinatorial approach exploiting solution NMR, flexible docking calculations, mutagenesis, and enzymatic studies. We provide evidence that an equimolar ratio of the cis and trans states of captopril exists in solution and that the enzyme selects only the trans state of the inhibitor that presents architectural and stereoelectronic complementarity with its substrate binding groove.

    PMID:
    16889963
    [PubMed - indexed for MEDLINE]

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