THE CONFORMATION OF AN INHIBITOR BOUND TO THE GASTRIC PROTON PUMP

Substituted imidazo[1,2-a]pyridines are pharmaceutically important sma ll molecule inhibitors of the gastric H+/K+-ATPase, the membrane-bound therapeutic target for peptic ulcer disease, A non-perturbing analyti cal technique, rotational resonance NMR spectroscopy, was used to meas ure a precise (to +/-0.2 Angstrom) distance between atomic sites in a substituted imidazo[1,2-a]pyridine, TMPIP, bound to H+/K+-ATPase at it s high-affinity site in the intact, native membrane, The structural an alysis of the enzyme-inhibitor complex revealed that the flexible moie ty of TMPIP adopts a 'syn-type' conformation at its site of action, He nce, the conformation of an inhibitor has been resolved directly under near-physiological conditions, providing a sound experimental basis f or rational design of many active compounds of pharmaceutical interest , Chemically restraining the flexible moiety of compounds like TMPIP i n the syn-type binding conformation was found to increase activity by over 2 orders of magnitude, Such information is normally only availabl e after extensive synthesis of related compounds and multiple screenin g approaches. (C) 1997 Federation of European Biochemical Societies.