Structural Biology

The steroids testosterone and dihydrotestosterone (DHT) are androgens that play an important role in the development and

maintenance of a variety of physiological responses such as male sexual function, bone density, muscle mass and strength.

Th e androgen receptor is a nuclear hormone receptor that is expressed in many tissues and is responsible for mediating the

actions of testosterone and DHT. Patients that have defects in the androgen receptor or have androgen defi ciencies can be

eff ectively treated with exogenous testosterone and other steroidal androgens as a hormone replacement therapy. Th e anabolic

eff ects of testosterone have shown benefi t in age related decline of bone density and muscle mass. However, the side eff ect profi le

of testosterone and other currently available anabolic steroids precludes their wide spread use and the chronic administration

of steroidal androgens is associated with potential serious side eff ects such as hepatotoxicity, prostate hypertrophy and cancer.

In addition, the oral bioavailability of testosterone is poor and the route of its administration is generally through topical

formulations. We will describe our eff orts to fi nd novel series of oral tissue selective androgen receptor modulators (SARM)

i.e., cyanopyrroles and indolines that selectively promote muscle growth while showing reduced androgenic eff ects on the

prostate and seminal vesicles. Using a docking approach, we were able to delineate the binding mode of these series and further

optimize the potency. An x-ray structure of a lead compound 7 bound to AR ligand binding domain revealed an interesting

electrostatically unfavorable interaction of the 3-fl uorophenol group with a carbonyl backbone of Leu704 residue. QM based

intermolecular potential calculation performed to understand the strength of this interaction along with ligand strain energy

calculations indicate a small energy penalty of ~0.6 kcal/mol paid by the ligand to adopt the bound state conformation