Use of Prophet and MMS-X Computer Graphics in the Study of the Cardiac Steroid Receptor Site of Na,K-ATPase

Many often conflicting models have been proposed to describe the biological roles of digitalis structure and conformation. This chapter discusses the use of prophet and MMS-X computer graphics in the study of the cardiac steroid receptor site of Na, K-ATPase. X-ray crystallography provides precise atomic coordinates for subsequent analysis of the NIH Prophet and MMS-X computer systems. The conformational flexibility of the molecules is examined with potential energy calculations for rotations of the bonds to the C-17 side group and to the first sugar. The structures are superimposed and distances among corresponding atoms are calculated in the chapter to provide a direct measure of the geometric differences. It has been reported that the relative position of the C-17 side-group carbonyl oxygen had a nearly perfect correlation with rat brain Na, K-ATPase inhibition. The chapter also presents few of the analogs examined, including the toad poison bufalin and the progestin chlormadinone acetate. MMS-X is used to generate van der Waals enclosure maps to represent apparent volumes required for the compounds at the “ouabain-binding site.”