A Universal Pterocarpan-Vinyl-Polyphenol Scaffold for Multi-Target Skin Therapeutics: Six-Cycle Bayesian Active Learning Identifies Six Multi-Target Leaders Across 14 Skin-Disease Targets

We report the discovery of a pterocarpan-vinyl-polyphenol scaffold family that acts as a universal molecular template across six independent skin-disease verticals (scar regeneration, pigmentation, alopecia, acne, photoaging, fibrosis cross-disease). Six members of this family were identified through six rounds of Bayesian active learning (R9–R14, 4, 597 cofold predictions integrated, 14 protein targets, 200-candidate pool size). All six leaders satisfy the multi-target leadership criterion (top-5 in 8+ of 14 targets) and demonstrate paper-tier 10 ns molecular dynamics stability (RMSD < 2. 0 Å) on RTX 5090 GPU. The expected-improvement (EI) acquisition function reached saturation at R12 (EI=0. 0077), confirmed across three additional cycles (R13 EI=0. 0077, R14 EI not greater than R13). The R12₄/R12₁1/R14₅ hydroxymethyl/methoxy variants, R12₂3 methyl ester (TYR/TYRP1 selective), R13₁3 prenyl variant (R11₀ + lipophilicity enhancement), and R11₀ trihydroxy parent constitute a structure–activity relationship rich enough to support multi-vertical formulation strategies. R15/R16 chromanol follow-up separates a systemic-safety fragment path from a topical-optimized analog path; the R15 triple-safe chromanol fragment remained dynamically stable across its top-3 cofold targets in 30 ns MD, while an 18-pair R16 topical chromanol 30 ns matrix across TGFB1, DCT, and TYR remained paper-tier stable, and the TGFB1 top-6 subset remained stable in 60 ns follow-up (max RMSD 1. 22 Å, max last-third mean 0. 96 Å). We discuss the six-leader family as in silico-validated lead candidates for Recover Korean Medicine Clinic's universal-skin-care vertical and define wet-lab follow-up via Tier 1 contract research organization (CRO). Keywords: Bayesian active learning, multi-target drug discovery, pterocarpan, skin therapeutics, Boltz-2, OpenMM molecular dynamics, scaffold hopping, Korean herbal medicine ---