Rational Structure-Based Drug Design and Optimization in the Ligand-Binding Domain of the Glucocorticoid Receptor-α

Abstract

Endogenous glucocorticoids (GCs) are involved in a range of endocrine functions including the metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as the maintenance of immunological, renal and skeletal homeostasis. There is a need to find agents that preserve the immune effects of GCs without side effects such as those affecting metabolism (diabetes), bone tissue (osteoporosis), muscles (myopathy), eyes and skin. In this review, we focus on the use of recent computational approaches in glucocorticoid receptor (GR) drug-design efforts for the determination of novel GR ligands. We examine a number of structure-based (e.g., homology modeling and docking) studies that have been implemented and evaluate their success. By the end of 2008, there had been limited achievements utilizing docking studies and no published successes in the area of virtual high-throughput screening. However, the availability of novel crystal structures and the use of induced-fit docking protocols are improving docking success rates and promising to aid the future delivery of nonsteroidal ligands.