MTD approach to quantitative structure-activity relationships for cardiotonic steroids.

Abstract

A minimal topological difference (MTD) approach is made to describe quantitative structure-activity relationships (QSAR) for the Na+, K+-ATPase inhibitory activity of cardiotonic steroids. The calculations take into account 20 derivatives of digitoxigenin, digoxigenin, and gitoxigenin with small substituents at different sites of the steroid backbone. A multiple correlation coefficient of r = 0.916 is obtained using the MTD and an indicator variable for the presence of a 15 beta substituent. The corresponding receptor map reveals receptor wall vertices in the C11, C12, C15, and C22 regions. Both 3 beta and 16 beta substituents are found to contain receptor cavity vertices. The MTD results are discussed with respect to lactone-ring conformational investigations presented and they are compared with findings of previous structure-activity studies.