Shikonin and its derivatives as selective modulators of the vitamin D receptor: A molecular framework for precision therapeutics in diabetic nephropathy

The vitamin D nuclear receptor (VDR), a ligand-activated transcription factor, is integral to renal physiology and is implicated in the pathogenesis of diabetic nephropathy (DN). Targeting VDR with small-molecule selective VDR modulators (SVDRMs) represents a novel therapeutic strategy to attenuate DN progression. This study investigated Shikonin, a bioactive naphthoquinone, and a series of rationally designed derivatives as potential VDR antagonists. A scaffold hopping approach using the ADMETopt web server generated 100 Shikonin-based analogs optimized for pharmacokinetic properties. Structure-based virtual screening using Glide XP and MM/GBSA energy filtering identified four top-ranked candidates: Shikonin, Derivative_02, Derivative_12, and Derivative_39. These compounds exhibited favorable binding free energies and key interactions within the VDR ligand-binding domain. Molecular dynamics simulations (500 ns) revealed that Derivative_02 and Derivative_12 exhibited superior structural retention and dynamic stability, with average ligand RMSD values under 2.5 Å. Shikonin showed high pose retention, while Derivative_39 displayed moderate flexibility, indicative of multistate binding. Free energy landscape (FEL) mapping and principal component analysis (PCA) showed that Shikonin and Derivative_02 confined the receptor into energetically favorable conformations, while Derivatives_12 and _39 promoted broader conformational sampling. MM/GBSA binding free energy decomposition revealed Derivative_12 as the most thermodynamically favorable (ΔG_bind = −59.48 ± 6.13 kcal/mol), driven by strong Coulombic and lipophilic interactions. Superimposition of extracted minima structures with initial docking poses confirmed RMSD values between 1.180 and 1.488 Å, indicating stable pose retention across all ligands. These results suggest that Shikonin and its derivatives, particularly Derivative_02 and Derivative_12, exhibit robust and energetically favorable binding to VDR. This work positions these compounds as strong candidates for further optimization and preclinical validation in the therapeutic targeting of DN.