Structure based in silico screening of natural Vitamin D analogs for targeted and safer treatment of resistant multiple sclerosis.

Multiple Sclerosis (MS) is a chronic autoimmune disorder that causes progressive neurological disability through demyelination of the central nervous system. Vitamin D deficiency has been linked to increased MS risk and activity, with adequate levels shown to modulate immune responses. However, many MS patients exhibit resistance to high-dose Vitamin D therapy, often due to impaired Vitamin D Receptor (VDR) activation, limiting its therapeutic effectiveness and increasing the risk of side effects. This study explores the potential of natural Vitamin D analogs as safer and more effective alternatives for MS patients unresponsive to standard therapy. A ligand library of 317 Vitamin D analogs was curated using structure-based research from Pharmit and PubChem, emphasizing structural similarity to Vitamin D. Molecular docking was conducted to assess binding affinity to the VDR, followed by ADMET profiling to evaluate pharmacokinetic properties. Standard therapies for MS, such as interferon-beta and glatiramer acetate, are limited by incomplete responses and side effects. Complex 3 (BCP23832; CID 134692690) and Complex 5 (163217-09-2; CID 131954606) demonstrated the highest binding affinities to the VDR, with docking scores of - 12.2 kcal/mol and - 12.1 kcal/mol and corresponding inhibition constants (Ki) of 1.13 nM and 1.33 nM, respectively, showed high binding affinity, favorable gastrointestinal absorption, and the ability to cross the blood-brain barrier. These compounds were further analyzed via 200 ns molecular dynamics (MD) simulations, which demonstrated strong and stable interactions with key VDR residues, such as ALA135 and HIS137. Both analogs formed consistent hydrogen bonds, exhibited low Root Mean Square Deviation (RMSD) values, minimal Root Mean Square Fluctuation (RMSF), and stable Solvent Accessible Surface Area (SASA), indicating robust ligand-receptor binding. Overall, these findings highlight Complex 3 and Complex 5 as promising natural Vitamin D analogs with potential to overcome limitations of high-dose Vitamin D therapy in MS. While computational results are encouraging, further experimental validation is essential to confirm their safety, efficacy, and therapeutic value in clinical settings.