Chiang Mai Journal of Science

Recent researches have discovered the emerging role of sirtuin 7 (SIRT7) in various diseases including cancers. However, it is currently the least studied isoform of all sirtuin members, and no inhibitor has been developed for the enzyme. Thus, this study attempts to analyze the behavior of inhibitor binding site of SIRT7 using homology modeling, docking study, and molecular dynamics simulation with various developed small molecule sirtuin inhibitors, and compare it with two morestudied isoforms, SIRT1 and SIRT2. Inhibitors acting as the false substrates of sirtuins were also included in the simulation. Equivalent binding site forming amino acids in the three isoforms were identified with multiple sequence alignment and observation of the 3D structure of complexes of the enzymes with selected inhibitors. The results suggest that the enzymes have similar features in their inhibitor binding sites and the inhibitors are predicted to take place in the proximity of the conserved catalytic histidine. Differences found in the inhibitor binding site forming pairs of SIRT7 and their interaction with elongation of SIRT7 N-terminal region makes a slight difference in its way in interacting with the inhibitor molecules. The results also indicate that false substrate inhibitors that are used for other sirtuins can also be developed for SIRT7. The knowledge about the binding site of SIRT7 as the initial hint to develop inhibitor molecules of SIRT7. The similarity and key differences with other isoforms in their interactions with inhibitor molecules can be utilized in the development of isoform-selective sirtuin inhibitors.