The conformation of an inhibitor bound to the gastric proton pump

David A. Middleton, Rachel Robins, Xiaolong Feng, Malcolm H. Levitt, Ian D. Spiers, Carl H. Schwalbe, David G. Reid, Anthony Watts

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Substituted imidazo[1,2-a]pyridines are pharmaceutically important small molecule inhibitors of the gastric H +/K +-ATPase, the membrane-bound therapeutic target for peptic ulcer disease. A non-perturbing analytical technique, rotational resonance NMR spectroscopy, was used to measure a precise (to ±0.2 Å) distance between atomic sites in a substituted imidazo[1,2-a]pyridine, TMPIP, bound to H +/K +-ATPase at its high-affinity site in the intact, native membrane. The structural analysis of the enzyme- inhibitor complex revealed that the flexible moiety of TMPIP adopts a 'syn- type' conformation at its site of action. Hence, the conformation of an inhibitor has been resolved directly under near-physiological conditions, providing a sound experimental basis for rational design of many active compounds of pharmaceutical interest. Chemically restraining the flexible moiety of compounds like TMPIP in the syn-type binding conformation was found to increase activity by over 2 orders of magnitude. Such information is normally only available after extensive synthesis of related compounds and multiple screening approaches.
    Original languageEnglish
    Pages (from-to)269-274
    Number of pages5
    JournalFEBS Letters
    Volume410
    Issue number2-3
    Publication statusPublished - 30 Jun 1997

    Keywords

    • Drag design
    • Membrane target
    • Peptic ulcer
    • Proton pump
    • Solid state NMR

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