In Silico Design, Molecular Docking and ADME/Toxicity Profiling of 3-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide Derivatives as Potential Acetylcholinesterase Inhibitors for Alzheimer’s Disease

Author

Mrs. Tamilarasi G, Priya M, Archana A, Ajin TS, Hameedhash R, Srimathi D, Sergin P


Abstract

 Introduction: Alzheimer’s disease (AD) is characterised by cholinergic deficit, and inhibition of acetylcholinesterase (AChE) remains a mainstay of symptomatic therapy. The 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold has been explored mainly for AMPA-receptor modulation, and its potential against AChE has not been examined systematically. The present study evaluated five 3-substituted derivatives (CPD 1–5; phenyl, 4-chlorophenyl, 2-phenylethenyl, 4-hydroxy-3-methoxyphenyl and furan-2-yl) in silico.

Materials and Methods: Molecular docking against human AChE (PDB ID: 4EY7) was performed with AutoDock Vina in PyRx and the complexes were analysed in BIOVIA Discovery Studio Visualizer. Physicochemical properties, pharmacokinetics and drug-likeness were predicted with SwissADME, and toxicity risks with OSIRIS Property Explorer.

Results and Discussion: Predicted binding affinities ranged from −8.6 to −10.8 kcal/mol. CPD 3 (2-phenylethenyl) ranked highest (−10.8 kcal/mol), forming π–π contacts with Trp86, Tyr337 and Trp286, hydrogen bonds with Arg296, Phe295 and Tyr124, and π–sulfur contacts with Phe338 and Phe297, thereby contacting residues of both the catalytic and peripheral anionic sites. CPD 5 (furan-2-yl) showed the highest ligand efficiency (0.58 kcal/mol per heavy atom). All five compounds showed zero Lipinski violations, high predicted gastrointestinal absorption and no PAINS or Brenk alerts, and no mutagenic, tumorigenic, irritant or reproductive-toxicity risk was flagged by OSIRIS. CPD 1–3 were additionally predicted to cross the blood–brain barrier.

Conclusion: These computational findings identify CPD 3 as the most promising lead for synthesis and enzymatic validation; they are predictions and do not establish inhibitory activity.



Keywords

acetylcholinesterase, Alzheimer’s disease, benzothiadiazine 1,1-dioxide, molecular docking, AutoDock Vina, SwissADME, OSIRIS.



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