Affinity Prediction of Shikonins Towards Sirtuins and the Requisite Structural Motifs for the Selective Inhibition of SIRT2 and SIRT3

Background: Shikonin and alkannin derivatives have various pharmacological activities with unknown mechanisms of action. Sirtuins are key intracellular enzymes involved in the cell cycle and metabolism and are ideal targets of therapeutic agents. Some evidence based on recent studies indicates that shikonins are possible modulators of sirtuins. Objective: In this study, an extensive computational workflow was utilized to assess the affinity of 27 different derivatives of shikonins towards SIRT1-6 as possible molecular targets. Methods: Molecular docking and dynamics simulation studies were performed, followed by MMPBSA analysis, and the results were compared with standard and selective sirtuin inhibitors. Subsequently, the scaffold hopping approach was used to find novel and more drug-like structures. Accordingly, the pharmacophoric features of 3,4-(Methylenedioxy)cinnamoyl alkannin in SIRT2 and SIRT3 were extracted and used for screening PubChem and Mcule databases. Results: The results indicated that 3,4-(Methylenedioxy)cinnamoyl alkannin is a potent SIRT2 and SIRT3 inhibitor and even more potent than the standard sirtuin inhibitors AGK2 and selisistat. The results successfully revealed some privileged fragments for the selective inhibition of SIRT2 and SIRT3. Conclusion: An indole or benzimidazole fragment linked to basic nitrogen through an amide would be an ideal structural feature for SIRT2 inhibition, and 3-methyl-2H-pyrazolo[3,4-b]pyridine was found to be a privileged fragment for optimal inhibition of SIRT3.