Computational Repurposing of Nilotinib and Radotinib as SIRT2 Inhibitors for Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) including Alzheimer’s and Parkinson’s disease involve progressive neuronal death, and current treatments are unsatisfactory. Sirtuin-2 (SIRT2), a NAD⁺ dependent deacetylase with roles in microtubule dynamics and redox regulation, has been suggested as potential druggable target for neurodegeneration. As part of this work, we conducted a virtual screening using the FDA-approved drugs library against the SIRT2 protein to discover potential inhibitors more potent than SirReal2. The binding energy and its interaction study concluded that Nilotinib and Radotinib exhibited higher bindings (-13.2 kcal/mol and  -12.8 kcal/mol) than SirReal2 (-11.8 kcal/mol) through the formation of crucial interactions with the catalytic residues located at binding and active sites. PASS analysis revealed anti neurodegenerative potential for both drugs. Long-time scale molecular dynamics (500 ns) simulations investigated structural stability of SIRT2-drug complexes with reduced RMSD and RMSF values compared to protein-ligand complexes from SirReal2 together with the maintained compactness within the protein. Principal component and free energy landscape analysis revealed that Nilotinib, Radotinib bound to SIRT2 in lower-energy conformation with limited movement than the higher dynamic fluctuations induced by SirReal2. Moreover, MMPBSA and DFT calculation also investigate the binding stability complexes. Taken together, our results demonstrate Nilotinib and Radotinib as potential lead drugs for repurposing toward the discovery of novel inhibitors of SIRT2 with therapeutic implications in neurodegenerative diseases. These crucial findings strongly recommended for further experimental validation through in vitro and in vivo analysis.