Short communication reveals R16 chromanol optimizes DCT stability, suggesting potential for drug development.
R16 optimized the R15 chromanol fragment toward a topical lead hypothesis by increasing skin-window compatibility while preserving a compact chromanol core. We evaluated six chloro/dimethyl analogs across TGFB1, DCT, and TYR using Boltz-2 cofolding, an 18-pair 30 ns OpenMM stability matrix, two 60 ns robustness panels, and 100 ns plus 200 ns anchor-triad follow-up. The top cofold row was r16_03_tgfb1 (R15_chromanol_Cl_pos9, OCC1COc2cc(O)c(Cl)cc2C1) with affinity probability 0.682. All 18 30 ns matrix entries were stable, the TGFB1 top-six 60 ns panel completed 6/6 stable, and the DCT/TYR representative 60 ns panel completed 3/3 stable. The 200 ns long-horizon anchor triad also completed 3/3 stable: TGFB1 R15_chromanol_Cl_pos9 max RMSD 0.71 A, DCT R15_chromanol_Cl_pos9 max RMSD 1.05 A, and TYR R15_chromanol_Cl_pos6 max RMSD 0.80 A. These data support an in-silico topical optimization hypothesis, not clinical efficacy, confirmed binding, composition novelty, or freedom to operate.
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Cheongwoo Han (2026) studied this question.
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