In Silico Evaluation of Escitalopram Derivatives for Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia. The NLRP3 inflammasome, a key mediator of inflammation, plays an important role in AD pathophysiology. Since SSRI derivatives are being investigated as potential therapeutic agents for AD, this study aimed to investigate the activity of escitalopram derivatives against NLRP3. Escitalopram derivatives were identified using SwissSimilarity and filtered according to their predicted ADME and toxicity profiles using SwissADME and pkCSM. The 16 selected compounds were evaluated by molecular docking against NLRP3 (PDB ID: 7ALV) using AutoDock Vina. The protein and ligands were prepared using AutoDock Tools 1.5.6, and docking results were evaluated based on predicted docking scores and ligand-protein interactions. Molecular docking identified compounds 5, 14, and 15 as the most promising for binding to NLRP3, with docking scores of -9.2, -8.7, and -8.1 kcal/mol, respectively, compared with -9.7 kcal/mol for the co-crystallized ligand RM5. The reliability of the docking protocol was confirmed by redocking the co-crystallized ligand RM5, with an RMSD value of 0.78 Å. Compounds 5, 14, and 15 did not reproduce the same interactions as RM5 but showed favorable interactions within the NLRP3 binding region. Compound 5 established conventional hydrogen bonds with Lys232 and Thr233, a π-cation interaction with His522, a π-π interaction with Trp416, and several hydrophobic interactions. Overall, these results suggest that the selected compounds can interact with NLRP3 through binding modes distinct from RM5, supporting further investigation as potential NLRP3-targeting compounds.