Structural Compatibility and Dynamic Behaviour of Elsholtzia Ketones in the CCT128930-Defined TRPM7 Vanilloid-like Region

Background/Objectives: Transient receptor potential melastatin 7 (TRPM7) is a multifunctional ion channel-kinase containing a structurally resolved vanilloid-like (VL) regulatory region. Elsholtzia ketone (EK) and dehydroelsholtzia ketone (DEK), major ketones of Elsholtzia ciliata essential oil, are associated with cardiovascular effects, but their molecular target spectrum remains incompletely defined. We investigated whether EK and DEK can access and maintain structurally plausible configurations within the CCT128930-defined TRPM7 VL region. Methods: The 2.45 Å cryo-EM structure of mouse TRPM7 bound to CCT128930 (PDB 8W2L; M05) was prepared in an explicit lipid membrane and subjected to restrained minimization. The workflow combined repeated M05 redocking, blind and focused docking, RICS-based within-ligand pose selection, pose clustering, property-matched decoy controls, and 100-ns explicit-membrane molecular dynamics (MD). Results: Minimization preserved the VL architecture and all 12 M05 reference contacts. Ten independent M05 redocking runs recovered native-like poses in every run (best direct heavy-atom RMSD, 0.567 Å), although these ranked only 8–10 by Vina energy. Blind docking independently sampled the VL region for M05, EK, and DEK. Focused docking identified recurrent EK and DEK pose families reproducing 10/12 M05 contacts (Jaccard = 0.833). Property-matched decoys reached comparable high-end contact similarity, showing that reference compatibility was not ligand-specific. During MD, M05 showed the strongest positional and contact retention, EK intermediate redistribution, and DEK greater copy-dependent heterogeneity. Conclusions: EK and DEK can adopt M05-compatible geometries within the TRPM7 VL region, providing experimentally testable structural hypotheses. However, docking similarity and RICS do not demonstrate affinity, selectivity, potency, or functional TRPM7 modulation.