Design, Optimization and in-Silico Evaluation of a Phyto-Synthetic Topical Serum of Saw Palmetto Extract, Minoxidil and Caffeine for Androgenetic Alopecia

Androgenetic alopecia (AGA) is the most common cause of progressive, non-scarring hair loss and is driven by the local conversion of testosterone to dihydrotestosterone (DHT) by steroid 5α-reductase type 2 (SRD5A2) in genetically susceptible scalp follicles. The two approved therapies, topical minoxidil and oral finasteride, are limited respectively by an irritant alcoholic vehicle with variable response and by systemic sexual side effects. In the present investigation, a phyto-synthetic topical serum co-delivering a standardized saw palmetto (Serenoa repens) liposterolic extract, minoxidil 5% and caffeine was rationally designed, and the mechanistic basis of the three actives was evaluated in silico. Molecular docking against human 5α-reductase 2 (PDB ID: 7BW1) was performed in AutoDock Vina 1.2.5, and the protocol was validated by re-docking the co-crystallized inhibitor finasteride, which reproduced the crystallographic pose with a heavy-atom RMSD of 1.50 Å. β-Sitosterol, the principal phytosterol of saw palmetto, bound the enzyme almost as strongly as finasteride (−10.12 versus −10.96 kcal/mol) and engaged both catalytic residues Glu57 and Tyr91, whereas oleic acid (−6.50), lauric acid (−5.54), minoxidil (−7.22) and caffeine (−6.28 kcal/mol) bound more weakly, confirming that minoxidil and caffeine act through complementary, non-5-AR mechanisms. RDKit-based ADMET profiling showed minoxidil and caffeine to be small, hydrophilic and fully Lipinski-compliant, while β-sitosterol was highly lipophilic (LogP 8.02) with the highest predicted skin permeability (log Kp 0.47 cm/h), favoring partitioning into the lipid-rich pilosebaceous unit. On this basis, a Carbopol 940 serum (1% w/w) containing propylene glycol (10% w/w) as penetration enhancer was designed as the lead formulation, and a 32 full factorial optimization, physicochemical evaluation, Franz-cell release and ICH stability program was defined for its experimental validation. This study provides a validated computational and formulation foundation for a multi-mechanism topical therapy for androgenetic alopecia.