The conformation of an inhibitor bound to the gastric proton pump

FEBS Letters

Feng, Xiaolong²  Schwalbe, Carl H.³  Watts, Anthony⁴  Levitt, Malcolm H.²  Spiers, Ian D.³  Middleton, David A.⁴  Robins, Rachel⁴  Reid, David G.¹ 

[1] Analytical Sciences Department, SmithKline Beecham Pharmaceuticals, Welwyn, Herts. AL6 9AR, UK;Physical Chemistry Division, Arrhenius Laboratory, University of Stockholm, S-10691 Stockholm, Sweden;Pharmaceutical Sciences Institute, Aston University, Birmingham B4 7ET, UK;Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX I 3QU, UK

关键词: Proton pump;    Drug design;    Membrane target;    Solid state NMR;    Peptic ulcer;   

DOI  :  10.1016/S0014-5793(97)00525-5

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown