新規合成ステロイド誘導体：アンドロゲン拮抗活性の標的予測と生物学的評価

Two natural steroids derived from cholesterol pathways are testosterone and progesterone, androgen and antiandrogen receptor binding. Steroid androgen antagonists can be prescribed to treat an array of diseases and disorders such as gender dysphoria. In men, androgen antagonists are frequently used to treat prostate cancer and hyperplasia. Sex hormones regulate the expression of the viral receptors in COVID-19 progression, and these hormones may act as a metabolic signal-mediating response to changes in glucose and Reactive Oxygen Species (ROS). The objective of the present study is to use artificial intelligence (AI) applications in healthcare to predict the targets and to assess biological assays of novel steroid derivatives prepared in house from the commercially available 16-dehydropregnenolone acetate (DPA^®) aimed at achieving the metabolic stability of glucose and steroid brain homeostasis. This suggests the introduction of aromatic or aliphatic structures in the steroid B-ring and D-ring. This is important since the roles of 5α-reductase and ROS in brain control of glucose and novel steroids homeostasis remain unclear.

A tool prediction was used as a tuned algorithm, with the novel steroid derivatives data in web interface to carry out their pharmacological evaluation. The new steroidal derivatives were determined with neuroprotection effect using the select biomarkers of oxidative stress on induced hypoglycemic male rat brain and liver. The enzyme kinetics was established by the inhibition of the 5α-reductase enzyme on the brain myelin.

We used novel chemical structures to order the information of a Swiss data bank that allow target predictions. Biological assays suggest that steroid derivatives with an electrophilic center can interact more efficiently with the 5α-reductase enzyme, and by this way, induce neuroprotection in hypoglycemia model. All compounds were synthesized with a yield of 30-80% and evaluated with tool target prediction to understand the molecular mechanisms underlying a given phenotype or bioactivity and to rationalize possible favorable or unfavorable side effects, as well as to predict off-targets of known molecules and to clear the way for drug repurposing. Apart, they turned out to be good inhibitors for the 5α-reductase enzyme.

The probed efficacy of these novel steroids with respect to spironolactone control appears to be a promising compound for future hormonal therapy with neuroprotection activity in glucose disorder status. However, further research with clinically meaningful endpoints is needed to optimize the use of androgen antagonists in these hormonal therapies in COVID-19 progression.