Receptor-based pharmacophore modelling for the discovery of Sirtuin 1 modulators in Alzheimer’s disease

Sirtuin 1 (SIRT1), a key member of the sirtuin protein family, plays a vital role in regulating cellular processes such as aging, transcription, apoptosis, and inflammation. Its neuroprotective properties have made it a target of interest in Alzheimer’s disease (AD) research. In this study, a structure-based pharmacophore modeling approach was employed to identify potential SIRT1 modulators as novel therapeutic candidates for AD. Using Discovery Studio 2.0, a pharmacophore model was generated and used to virtually screen a compound library comprising 170,200 molecules from the NCI database and 191 plant-derived compounds. From this screening, 297 NCI and 160 plant-based compounds matched the pharmacophore features. Subsequent molecular docking identified four compounds-NCI169, NCI249, PSCdb00009, and PSCdb00016-with favourable binding affinities, showing docking scores of -11.5, -10.5, -10.0, and -10.1 kcal/mol, respectively. Molecular dynamics simulations confirmed the stability of these ligand-receptor complexes over a 100 ns timeframe, with RMSD values ranging from 1.92 to 2.7 Å. Additionally, Density Functional Theory (DFT) analysis revealed strong interactions with key polar amino acids, supporting the observed binding affinities. These findings suggest that the identified compounds are promising SIRT1 modulators and merit further biological evaluation for potential use in AD therapy. This integrative in silico strategy offers valuable insights into future drug development efforts targeting SIRT1.