Multi-target evaluation of Korean herbal compounds against the SRD5A2 / AR / beta-catenin axis for androgenetic alopecia: Boltz-2 cofold, ChEMBL-anchored ranking, ADMET-AI 107-endpoint safety panel, and pilosebaceous single-cell atlas-constrained prioritization of Saponin Re, Emodin, and Biochanin A

Androgenetic alopecia (AGA) is driven by androgen-pathway enzymes (SRD5A1/2 catalyzing testosterone to dihydrotestosterone), the androgen receptor (AR), and the hair-follicle-cycle Wnt / beta-catenin axis, with emerging evidence for mechanotransduction (PIEZO1 / MLCK) as a non-androgen contributor to follicular miniaturization. Korean traditional medicine documents hair-vitalization preparations centered on Polygonum multiflorum (Hasuo; emodin, physcion), Astragalus membranaceus (Hwanggi; astragaloside IV), and Panax ginseng (Insam; ginsenosides Rg1, Rb1, Saponin Re), among others. We evaluate a 15-compound curated Korean herbal library against the SRD5A2 / AR / CTNNB1 (beta-catenin) three-target panel using a four-layer in silico framework: (i) Boltz-2 protein-ligand co-folding with cached MMseqs2 multiple-sequence alignments (n = 39 successful cofolds, 6 SMILES sanitization or fold failures explicitly listed) ; (ii) a ChEMBL pIC50 calibration anchor carried over from the parallel MMP-1 calibration set (Pearson R = -0. 453, n = 93), establishing that Boltz-2 affinityₚrobabilitybinary is a relative-ranking predictor and not an absolute potency estimate; (iii) ADMET-AI v2. 0. 1 safety prediction across 107 endpoints including hERG, skin reaction, AMES, and ClinTox; and (iv) cell-type filtering against an 821k-cell pilosebaceous single-cell atlas (cross-link to the companion PIEZO1 / MLCK repositioning study), restricting downstream prioritization to compounds whose targets are expressed in the dermal papilla and connective-tissue-sheath cell populations relevant to AGA pathobiology. SRD5A1 was not folded (cached MSA absent) and is an explicit limitation. Boltz-2 results identify Saponin Re from Panax ginseng and Emodin from Polygonum multiflorum as joint top-1 by mean affinity (mean 0. 675 each), with Saponin Re leading SRD5A2 (0. 746) and Emodin leading AR (0. 768). Both leads carry explicit trade-offs: Emodin (skin reaction 0. 957, AMES 0. 711) and Physcion (skin reaction 0. 921, AMES 0. 734) carry significant safety flags; Saponin Re (MW 947, logP -0. 03) is far outside the topical sweet spot. Biochanin A from soy and Astragalus membranaceus emerges as the cleanest combined-profile candidate (mean 0. 544, hERG 0. 52, AMES 0. 24, topical-friendly). Finasteride, the reference SRD5A2 inhibitor, ranks low in the Boltz-2 binary classifier (mean 0. 202), reflecting the classifier's known limitation for mechanism-based covalent inhibition; this is a methodological observation, not a refutation of finasteride's clinical efficacy. Open Targets evidence-tier mapping places SRD5A2, AR, and CTNNB1 in the green-evidence tier for AGA. We position Biochanin A, Saponin Re, and Emodin as topical-scalp candidates with explicit safety-versus-affinity trade-offs whose forward path is dermal papilla cell culture and three-dimensional scalp organoid validation. All findings are in silico; no experimental potency, no clinical claim, and no commercial product is reported. Code, raw cofold JSON, ADMET predictions, and atlas-filter outputs are released under Apache-2. 0. Keywords: androgenetic alopecia, 5-alpha-reductase, SRD5A2, androgen receptor, Wnt beta-catenin, Korean traditional medicine, multi-target in silico evaluation, Boltz-2 cofold, ChEMBL calibration anchor, ADMET-AI, pilosebaceous single-cell atlas, Biochanin A, Saponin Re, Emodin. ---