Prostate cancer (PCa) progression is mediated by androgen receptor (AR) agonists. The AR drives cellular proliferation following activation by native androgen ligands (testosterone and 5𝛼- dihydrotestosterone (DHT)). Prevention of AR activation can limit PCa cell proliferation; this can be achieved by starving the receptor of its native ligands and/or using antagonistic androgen mimics (e.g., bicalutamide) – this is the basis of PCa treatment.

In an androgen-free environment, there is a risk that ARs might be activated by agonistic androgen mimics. Agonists usually have structural similarities with native receptor ligands, thus leading to receptor activation. Some steroid-based drugs with structural similarities to native AR ligands are used in PCa treatment.

The research aimed to study interactions between the AR and potential androgen mimics that are used in PCa treatment. AR-ligand interactions were studied in silico using molecular docking and dynamics simulations in the Schrödinger platform and then to explore the effects of identified androgen mimics on PCa cell (22Rv1) proliferation in culture. The natural ligands testosterone and DHT, the first-line PCa antagonist treatment, bicalutamide, and the potential ligand mimics (used as adjuncts to PCa treatment) hydrocortisone, dexamethasone, oxandrolone, triamcinolone, and prednisone were studied. In addition, since 22Rv1 is a new cell line to our research group and little is known of its growth in the literature, its growth characteristics were studied.

All ligands, including the AR antagonist bicalutamide, interacted with amino acid residues Asn705 and Thr877, which are known to be important for AR activation; however, they only resulted in weak stimulation of 22Rv1 proliferation. Interestingly, the growth characteristics and morphology of 22Rv1 changed, which suggests the selection of clones as the experimental work progressed; this is not unexpected because PCa is characterised by cancer cell de-differentiation and eventual lack of response to androgens.