Silent
mating-type information regulation 2 homologue 1 (SIRT1),
being the homologous enzyme of silent information regulator-2 gene
in yeast, has multifaceted functions. It deacetylates a wide range
of histone and nonhistone proteins; hence, it has good therapeutic
importance. SIRT1 was believed to be overexpressed in many cancers
(prostate, colon) and inflammatory disorders (rheumatoid arthritis).
Hence, designing inhibitors against SIRT1 could be considered valuable.
Both structure-based and ligand-based drug design strategies were
employed to design novel inhibitors utilizing high-throughput virtual
screening of chemical databases. An energy-based pharmacophore was
generated using the crystal structure of SIRT1 bound with a small
molecule inhibitor and compared with a ligand-based pharmacophore
model that showed four similar features. A three-dimensional quantitative
structure–activity relationship (3D-QSAR) model was developed
and validated to be employed in the virtual screening protocol. Among
the designed compounds, <b>Lead 17</b> emerged as a promising
SIRT1 inhibitor with IC<sub>50</sub> of 4.34 μM and, at nanomolar
concentration (360 nM), attenuated the proliferation of prostate cancer
cells (LnCAP). In addition, <b>Lead 17</b> significantly reduced
production of reactive oxygen species, thereby reducing pro inflammatory
cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory
potential of the compound was ascertained using an animal paw inflammation
model induced by carrageenan. Thus, the identified SIRT1 inhibitors
could be considered as potent leads to treat both cancer and inflammation