System among the corticosteroids: Specificity and molecular dynamics

J.C. BROOKES, M.D. GALIGNIANA, A.H. HARKER, A. M. STONEHAM, G.P. VINSON

JOURNAL OF THE ROYAL SOCIETY INTERFACE

ROYAL SOC

Año: 2011

1742-5689

Understanding how structural features determine specific biological activities has often proved elusive. With over 161000 steroid structures described, an algorithm able to predict activity from structural attributes would provide manifest benefits.             Molecular simulations of a range of 35 corticosteroids show striking correlations between conformational mobility and biological specificity. Thus steroid ring A is important for glucocorticoid action, and is rigid in the most specific (and potent) examples, such as dexamethasone. In contrast, ring C conformation is important for the mineralocorticoids, and is rigid in aldosterone. Other steroids which are less specific, or have mixed functions, or none at all, are more flexible. One unexpected example is 11-deoxycorticosterone, which the methods predict (and our activity studies confirm) is not a specific mineralocorticoid, but also has significant glucocorticoid activity. These methods may guide the design of new corticosteroid agonists and antagonists. They will also have application in other examples of ligand-receptor interactions.