ABSTRACT:
Background: Male infertility contributes to approximately 50% of infertility cases globally, with oxidative stress and environmental exposures increasingly implicated in its rising prevalence. Despite this burden, research targeting androgenic phytotherapy remains limited. Triclisia subcordata Oliv. (Menispermaceae) is a West African medicinal plant with documented ethnomedicinal application in male reproductive health, yet its fertility-enhancing mechanisms at the molecular and receptor level remain uncharacterised. Objectives: This study aimed to determine the phytochemical composition, in silico androgen receptor binding affinity, antioxidant potential, cytotoxicity, and reproductive effects of the aqueous–ethanol root extract of T. subcordata using integrated pharmacological and computational approaches. Methods: Authenticated root of T. subcordata Oliv. (Voucher No. UIH-23535) was cold-macerated in 65:35 water–ethanol. Phytochemical screening, GC–MS profiling, DPPH radical scavenging assay, and brine shrimp lethality assay (BSLA) were conducted. Molecular docking against the human androgen receptor was performed using the Glide module of the Schrödinger Maestro Suite with SiteMap active site prediction. Reproductive activity was evaluated using Drosophila melanogaster mating and fertility assays at 10 and 100 ppm, with sildenafil as the positive control. Results: Extraction yielded 2.00% dry extract containing alkaloids, flavonoids, and steroids. GC–MS identified methyl benzoate (95.49%), phenol (1.66%), and 3-methylpyridazine (1.55%) as the principal constituents. Molecular docking revealed that both compounds achieved binding scores comparable to or exceeding the reference ligand at androgen receptor active sites 1 and 2, with drug-likeness parameters satisfying Lipinski’s Rule of Five. The extract demonstrated moderate antioxidant activity (IC50 = 440.24 µg/mL) and was classified as non-toxic by BSLA (LC50 = 2,254 ppm). In D. melanogaster assays, offspring emergence was enhanced at both doses, indicating fertility-promoting activity independent of aphrodisiac effects. Conclusion: The aqueous–ethanol root extract of T. subcordata demonstrates promising androgenic and fertility-enhancing properties supported by favourable in silico androgen receptor interactions, moderate antioxidant activity, and a wide safety margin. Controlled pre-clinical and clinical studies are recommended to validate therapeutic efficacy and establish optimal dosing parameters..