TY - JOUR T1 - A Crystallographic, Conformational Energy, and Biological Study of Actodigin (AY-22,241 ) and Its Genin JF - Molecular Pharmacology JO - Mol Pharmacol SP - 43 LP - 51 VL - 17 IS - 1 AU - DWIGHT S. FULLERTON AU - KOUICHI YOSHIOKA AU - DOUGLAS C. ROHRER AU - ARTHUR H. L. FROM AU - KHALIL AHMED Y1 - 1980/01/01 UR - http://molpharm.aspetjournals.org/content/17/1/43.abstract N2 - A multidisciplinary (crystallographic, conformational energy, biological) study of Actodigin and digitoxigenin was completed, and the data analyzed using the NIH PROPHET computer system. These data were compared to Na+,K+-ATPase inhibition studies on Actodigin genin, digitoxigenin β-D-glucoside, digitoxin, and digitoxigenin β-D-digitoxide. This work has shown that Actodigin genin’s ability to inhibit Na+,K+-ATPase can be largely explained by its lactone carbonyl oxygen position (5.22 Å displaced from the carbonyl oxygen of digitoxigenin, both molecules in their crystallographically observed energy minima) and molecular conformation. The ring D of Actodigin, for example, was found to be in a half chair, unlike those of natural digitalis ring D’s, which exist in an envelope. However, the β-D-glucose makes an unexpectedly large contribution to Actodigin’s activity—much larger than with digitoxigenin glucoside. Actodigin genin has very low activity (I50 7 x 10-5 M), nearly the least active genin we have studied. These findings were not predicted by a recently proposed Actodigin binding model, and they give new insight into the glycoside binding model proposed by Yoda and Yoda. ACKNOWLEDGMENTS We thank Gregory Quarfoth and Ms. Renae Roelofs for their excellent technical assistance in the biological studies; Dr. Romano Deghenghi, Director of Research, Ayrest Laboratories, for providing samples of AV-22,241 and its acetate; and Professor A. Schwartz for a prepublication copy of his Actodigin study (2). The organization and analysis of the data base associated with this investigation were carried out in part using the PROPHET system, a unique national resource sponsored by NIH. Information about PROPHET can be obtained from the Director, Chemical/Biological Information Handling Program, Division of Research Resources, NIH, Bethesda, Maryland 20014. ER -