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, Lead 17 emerged as a promising
SIRT1 inhibitor with IC50 of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of
prostate cancer cells (LnCAP). In addition, Lead 17 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.