Mapping the structural requirements for SIRT2 inhibition: Insights from a diverse in-house library and 3D-QSAR...

Selective inhibitors of the nicotinamide adenine dinucleotide (NAD⁺)-dependent lysine deacylase sirtuin 2 (SIRT2) have emerged as promising therapeutics, as SIRT2 is increasingly recognized as a critical regulator in the pathogenesis of cancer and neurodegenerative diseases. Moreover, the development of selective SIRT2 inhibitors provides valuable insights into the physiological and pathophysiological roles of this enzyme, thereby contributing to both mechanistic understanding and therapeutic strategies for these disorders. Accordingly, our sustained efforts to identify selective SIRT2 inhibitors have resulted in a structurally diverse in-house library of small-molecule compounds. In this study, the inhibitory activities of 69 in-house compounds were evaluated as percentage inhibition at a fixed concentration of 100 µM and converted to a logarithmic scale to serve as a screening metric for a three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling. The generated 3D-QSAR model, based on molecular field analysis, yielded statistically significant results (R²=0.8251, Q²=0.7888, and Pearson-r = 0.8917) and enabled the identification of key structural features responsible for inhibitory activity. Our findings highlight the significance of steric and hydrophobic features in SIRT2 inhibition. Furthermore, the generated contour maps indicated favorable and unfavorable regions for incorporating electrostatic, hydrogen bond acceptor (HBA), hydrogen bond donor (HBD) groups, and aromatic rings to improve the targeted activity.