In silico-guided exploration of SIRT6 modulation: Discovery of new fragments hits inhibitors

Sirtuin 6 (SIRT6) has recently gained significant attention due to its dual role in various cancers and its involvement in crucial biological processes such as DNA damage repair, telomere maintenance, and metabolic regulation. Despite this, selective modulation of SIRT6 remains challenging, particularly regarding developing potent inhibitors. This study involved a combination of computational approaches to gain insights into the molecular mechanism of action of SIRT6 and try to identify new potential inhibitors through a virtual screening of over 25,000 molecules. We examined the structural interactions of known SIRT6 modulators using docking, molecular dynamics simulations, and binding pose metadynamics. Due to the recent findings on the SIRT6 inhibition in cancer and inflammatory diseases, we focused our attention on the inhibitors. After a structural study of the target, a fragment virtual screening (VS) allowed us to select a set of promising compounds to validate in vitro. Compounds 9, 10, and 13 were the most suitable for a fragment-growth strategy, paving the way for the design and synthesis of new anticancer agents targeting SIRT6.