Hormones are ideal targets for rational drug design. Since hormones are precise
chemical messengers influencing specific metabolic function throughout the body, their
pharmacological manipulation by the administration of either agonists or antagonists
permits therapeutic modulation of a wide range of biochemical events. Moreover, since
many hormones are small molecules (i.e., steroids or short peptides with molecular
weights less than 1000) they are readily studied using molecular modeling calculations
to facilitate rational drug design. When broadly categorized on a molecular basis, hor-
mones may be either steroid-based or peptide-based. Both categories have been and
continue to be widely exploited for purposes of drug design. This chapter examines the
role of both steroid hormones (sections 5.2–5.13) and peptide hormones (sections
5.14–5.23) in drug design.
5.2 STEROID HORMONES: INTRODUCTION
The steroid hormones include the sex hormones (estrogens, progestins, androgens) and
theadrenocorticoids(glucocorticoids, mineralocorticoids), as well as their biosynthetic
precursor, cholesterol. Steroid hormones are based on the four-ring steran (5.1) carbon
skeleton. Other pharmacologically interesting steroids, like the heart-active cardeno-
lides, are compounds of plant origin.
Minor changes in the stereochemistry and substitution pattern of the steran skeleton
result in vastly different yet specific physiological and pharmacological effects, which
in turn influence developmental, metabolic, and behavioral phenomena. The organic
chemistry and biochemistry of steroids is the subject of many excellent books and an
enormous amount of research and patent literature. This chapter compares and contrasts
the structure and mode of action of various steroids, their role in regulating hormonal
secretion, and the timing of this regulatory action.
One of the most unique and powerful features of steroid hormones is the nature of
the steroid receptor. Unlike most other hormones or drugs, which target protein recep-
tors usually embedded in membranes, steroids target the genes themselves, buried deep
within the nucleus of the cell.
5.3 STEROID HORMONES: RECEPTOR BIOCHEMISTRY
Steroid receptors are highly specific macromolecules found in central regulatory organs
(e.g., pituitary, hypothalamus), in various end-point target tissues (e.g., uterus, vagina,
prostate), and in lower concentrations in the brain, liver, kidney, ovary, and many other
organs. Steroid hormones exhibit remarkable tissue selectivity when binding to these
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