Glycyrrhiza Phytochemicals as Candidate Ligands of Skeletal Muscle Metabolic Regulators: An Integrative Reverse-Docking and Replicate Molecular Dynamics Study

Background/Objectives: Skeletal muscle (SM) is a major site of insulin-stimulated glucose disposal, and impaired muscle metabolism contributes to insulin resistance. Glycyrrhiza constituents warrant investigation as potential modulators, but many compound–target relationships remain uncharacterized. We sought to prioritize hypotheses involving eight muscle-metabolic regulators. Methods: A 100-compound library selected from 838 LOTUS records was screened against eight crystallographic receptor models (800 pairs). Within-target ranking and chemical triage prioritized five pairs for three-seed focused docking and three independent 500 ns molecular-dynamics replicas each (7.5 μs total). Original-site ligand displacement and contact retention were examined alongside MM/PBSA estimates from previously selected windows and a common 400–500 ns interval. Results: Native-ligand redocking recovered a pose within 2 Å for every receptor; the top-ranked pose met this criterion for six of eight. Shinpterocarpin–PPARδ, semilicoisoflavone B–p38α MAPK and LTS0113182–PPARα showed the most consistent original-site residence (mean docked-pose RMSD, 0.157–0.359 nm over 400–500 ns). LTS0135332–PPARδ showed greater displacement (0.581 nm) and replica-dependent contact loss. Kanzonol B–PTP1B relocated in two replicas (mean RMSD, 2.489 ± 1.857 nm). Common-window MM/PBSA means ranged from −146.0 to −76.1 kJ mol−1. For PTP1B, the historical selected-window mean was −107.7 kJ mol−1, illustrating interval sensitivity rather than an affinity ranking. Conclusions: The analyses support three comparatively consistent binding hypotheses, one mixed PPARδ result, and one lower-confidence PTP1B result. Binding and target-specific functional assays are required; the calculations do not establish target modulation or SM efficacy.