An Approach to Greater Specificity for Glucocorticoids

Area of Science:

• Pharmacology
• Molecular Biology
• Biophysics

Background:

• Glucocorticoid steroids are widely prescribed but suffer from poor selectivity and numerous side effects.
• Previous research to enhance glucocorticoid specificity has been limited by complex gene regulation and lack of predictable properties.
• Correlations with steroid structure, receptor/chromatin conformation, DNA binding, and cofactors have not yielded guidance for specificity.

Purpose of the Study:

• To present a novel mathematical theory for a quantifiable approach to increase glucocorticoid selectivity.
• To apply this theory to agonist and antagonist actions on glucocorticoid receptors, including gene induction and repression.
• To provide guidance for developing more specific glucocorticoid-based therapeutics.

Main Methods:

• Summarizing a mathematical theory for glucocorticoid action.
• Utilizing simple graphical analysis of competition assays with various factors (steroids, chemicals, peptides, proteins, DNA).
• Analyzing kinetic mechanisms and relative action steps of different factors.

Main Results:

• Competition assays yield information on the kinetic mechanism and action step of each factor.
• This data provides a clear direction for enhancing glucocorticoid specificity.
• Varying concentrations of cofactors/pharmaceuticals acting closest to the endpoint is most promising for selectivity.

Conclusions:

• The mathematical theory offers a quantifiable method to improve glucocorticoid selectivity.
• Understanding the kinetic mechanism and action steps guides the development of more specific drugs.
• Combining cofactor/antagonist concentration adjustments offers significant potential for enhanced specificity.