QSAR, molecular docking, MD simulations, and ADMET screening identify potential leads against key targets in benign prostatic hyperplasia.

Unlabelled: Steroid 5α-reductase (5αR) converts testosterone into dihydrotestosterone (DHT), a potent androgen driving prostate cell proliferation via the androgen receptor (AR). Both 5αR and AR play crucial roles in androgen-mediated disorders, making them key therapeutic targets in drug development. Current treatments target these enzymes individually and often cause significant side effects, highlighting the need for safer alternatives. Through screening, 13 pyrrolizidine alkaloids of (HI) were assessed for their inhibitory potential against 5αR and AR. Using machine learning, six alkaloids showed promising pIC50 values. The accuracy of the models was assessed using key statistical parameters, including the score, correlation coefficient for training sets (R), correlation coefficient for test sets (Q), standard deviation (SD), and root mean square error (RMSE). For 5αR, the results were 0.763 (R), 0.781 (Q), 0.748 (score), 0.362 (SD), and 0.832 (RMSE), while for AR, the values were 0.817 (R), 0.783 (Q), 0.713 (score), 0.427 (SD), and 0.782 (RMSE), indicating reliability. Europine-N-oxide (-10.27 kcal/mol) and Heliotridine-N-oxide (-9.72 kcal/mol) displayed stronger 5αR binding than Finasteride, while Heliotrine (-10.09 kcal/mol) and Europine-N-oxide (-8.76 kcal/mol) outperformed Enzalutamide in AR binding. Key hydrogen bonds and MD simulations confirmed stable interactions. Pharmacokinetic screening revealed favorable drug-like profiles, including good solubility and absorption with minimal CYP enzyme inhibition. These findings suggest that HI alkaloids are promising multi-target inhibitors for BPH treatment, warranting further in vivo validation and optimization.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00280-7.