Organotins as inhibitors targeting human and rat steroid 5α-reductase 1: structure-activity relationship and docking analysis

Steroid 5α-reductase 1 (SRD5A1) catalyzes the conversion of testosterone to dihydrotestosterone, playing crucial roles in steroidogenesis in the brain and reproductive system. This study aimed to systematically evaluate the inhibitory effects and mechanisms of action of organotins on human and rat SRD5A1. Sixteen organotins were screened for the inhibitory strength and enzyme inhibition assays, molecular docking, and correlation analyses were performed. Among the tested compounds, dipropyltin, diphenyltin, triethyltin, tributyltin, and triphenyltin significantly inhibited human SRD5A1 with IC₅₀ values of 30.31, 17.83, 28.28, 12.69, and 4.38 μM, respectively. Dioctyltin, tributyltin, tetrapropyltin, and tributylphenyltin also markedly inhibited rat SRD5A1 with IC₅₀ values ranging from 11.91 to 29.96 μM. These organotins exhibited mixed/noncompetitive inhibition with respect to testosterone and bound to the NADPH-binding site of SRD5A1, forming interactions with critical methionine residues. Dithiothreitol partially reversed inhibition by triphenyltin, suggesting that interaction with the sulfhydryl group of methionine mediates inhibition. In SF126 cells, diphenyltin, triphenyltin, and triethyltin significantly reduced dihydrotestosterone production at ≥ 1 μM. Correlation analysis indicated that molecular weight, heavy atoms, and LogP were correlated with inhibitory potency against SRD5A1. These findings elucidate the structure-activity relationships and mechanisms by which organotins inhibit SRD5A1, highlighting their potential to disrupt steroidogenesis and neurosteroid biosynthesis, with implications for reproductive and neurological health.