Computational &Experimental Structure-Activity Relationships of Digoxin Analogues

A better understanding of interactions between cardiac glycosides and Na/K-ATPase is required for better drug development for the treatment of congestive heart failure. Current drug therapy includes the use of cardiac glycosides which inhibit the sodium/potassium ATPase (Na/K-ATPase) enzyme causing myocardial cells to pump harder and more efficiently. Many cardiac glycosides excessively inhibit the Na/KATPase enzyme which can cause toxic side effects. Therefore more research is required to specify the molecular interactions between Na/K-ATPase and the cardiac glycoside. Since the lactone functional group is the most active part of the cardiac glycoside, modifications at this site have the highest potential for modulating inhibition. Modifications to the lactone ring are originally visualized by modeling digoxin analogues from the literature. Compounds are subjected to energy minimization techniques and aligned according to a shared steroid backbone. The effects of such modifications are then analyzed by comparative field analysis (CoMFA) and comparative field similarity index analysis (CoMSIA). CoMFA and CoMSIA contour plots highlight regions that are affected by changes in steric bulk, electrostatics, hydrogen bonding, and hydrophobicity. The contour maps indicate the type and location of the compound-enzyme interactions by generating three-dimensional images around the compound. Molecules with the desired modifications are inserted into the models and their activities are predicted. Compounds with high predicted bio-activities will be purchased and evaluated experimentally. Ultimately, this knowledge will aid in the synthesis of novel and safer drugs for the treatment of congestive heart failure