[DARC/PELCO structure activity relationships of aldosterone agonists and antagonists]

To detect the sites essential for binding affinity, we use the DARC/PELCO topological correlation search method and apply it to 52 17-spirolactone or 17-hydroxymethylcarbonyl steroids, aldosterone agonists or antagonists. The optimal model explains 98% of the total variance with a precision close to experimental. The main favourable contributions come from direct substitutions on rings C and D of the steroidal skeleton, the most unfavourable from those on rings A and B. The secondary structural modifications - modifications of existing substituents or second substitutions on the focus - have a slight deactivating influence, except the simultaneous existence of two contiguous double bonds on the 11 beta chain. Structures predicted to have a high affinity are built up by combining the most favourable structural elements: 9 alpha-F, 11 beta-allenyl, delta 11, 12 and 15 beta-, 16 beta-CH2. Some are predicted to have an affinity 100- to 1000-fold higher than aldosterone.