QSAR, Molecular Docking, MD Simulations, and ADMET Screening Identify Potential Heliotropium indicum Leads against Key Targets in Benign Prostatic Hyperplasia

Steroid 5 alpha-reductase (5αR) is a membrane-embedded enzyme responsible for converting testosterone into the more potent androgen, dihydrotestosterone (DHT), within the prostate. The androgen receptor (AR), in turn, mediates DHT's effects by regulating genes critical to cell proliferation and survival. Both 5αR and AR play pivotal roles in the development and progression of Benign Prostatic Hyperplasia (BPH), making them prime therapeutic targets for drug discovery. Unfortunately, no current drugs simultaneously target both enzymes, and existing treatments for either often lead to significant side effects, emphasizing the urgent need for safer, more effective alternatives. Through in silico screening, 13 pyrrolizidine alkaloids were evaluated for their inhibitory potential against 5αR and AR. The top six alkaloids — Heliotrine, Europine-N-oxide, Heleurine-N-oxide, Lasiocarpine, Indicine, and Heliotridine-N-oxide — exhibited promising pIC50 values. Notably, Europine-N-oxide (-10.27 kcal/mol) and Heliotridine-N-oxide (-9.72 kcal/mol) demonstrated stronger binding affinities to 5αR compared to the standard drug, Finasteride (-9.66 kcal/mol). Similarly, Heliotrine (-10.09 kcal/mol) and Europine-N-oxide (-8.76 kcal/mol) outperformed the standard AR blocker, Enzalutamide (-8.21 kcal/mol). Key hydrogen bonds were revealed, with Europine-N-oxide forming interactions with residues Tyr91, Arg94, Tyr98, and Glu197 in 5αR, while Heliotrine engaged with Asn160, Asp164, Glu57, and Arg94. MD simulations confirmed more stable and favorable interactions between the ligands from Heliotropium indicum (HI) and the targets compared to the standard drugs. Furthermore, pharmacokinetic screening highlighted high solubility, strong intestinal absorption, and minimal CYP enzyme inhibition, indicating favorable drug-like profiles. In conclusion, this study identifies HI alkaloids as promising multi-target inhibitors for BPH treatment. These findings warrant further in vivo validation and structural optimization to fully unlock their therapeutic potential in managing BPH