Insights from computational studies about structural determinants of steroidal inhibitors in 5-alpha-reductase type II

5-alpha-reductase type II (5αR2) is an important protein involved in the reduction of testosterone to dihydrotestosterone, a product that promotes prostate growth and can lead to conditions such as prostate cancer and benign prostatic hyperplasia. This study presents a computational analysis of steroidal compounds with close structural relationships but notable differences in their biological activity. A set of molecules with reported half-maximal inhibitory concentrations, obtained under consistent conditions, was selected, and molecular docking and molecular dynamics simulations were performed. Considering the covalent inhibition mechanism of this protein, key atomic distances, root mean square deviations, and binding free energy were investigated to explain the significant differences in biological activity. The data suggest that the key to inhibitory capacity lies in the conformation that optimally facilitates bond formation between the NADPH cofactor and the α,β-unsaturated system of the inhibitors within the 5αR2 pocket. Considering that the protein pocket is rich in hydrophobic residues, introducing an atom such as fluorine, which increases the hydrophobicity of the ligand, may alter the favorable conformation within the pocket. This, in turn, could compromise the ability of the ligand to form a covalent bond with NADPH. Given the covalent nature of the inhibition mechanism, stability within the catalytic site plays a secondary role. Understanding these structural features is crucial for designing new potential 5αR2 inhibitors, particularly steroidal compounds, that aim to leverage a covalent mechanism of inhibition.