IDENTIFYING POTENTIAL SIRT2 INHIBITORS: AN IN-SILICO APPROACH TO EXPLORE NOVEL STRATEGIES FOR PARKINSON’S THERAPY

Abstract

Aim: This study aims to identify and characterize potential SIRT2 inhibitors via computational approach.as an alternate therapeutic approach towards Parkinson’s. SIRT2 is positioned second in class III HDAC family of sirtuins and NAD+ (nicotinamide adenine dinucleotide) dependent in nature. SIRT2 plays a crucial role in neurodegeneration leading to diseases like Parkinson’s disease (PD). Therefore, the need to discover SIRT2 inhibitors aligns itself with potential therapeutic developments for treating PD. As a result of SIRT2 inhibition, α-synuclein (α-Syn) induced toxicity decreases leading to reduction in cell death. SirReal2 is a native SIRT2 inhibitor. It is situated in the selectivity pocket which is hydrophobic in nature present near the zinc binding domain (ZBD). SirReal2 was taken as the reference ligand for this study. The primary objective is to shortlist better suited compounds for SIRT2 inhibition as potential drug components for Parkinson’s therapy in comparison to what was deduced in previous such studies. Here, a large number of compounds will be shortlisted on the basis of structural similarity to SirReal2 which will then be filtered by ADME analysis. As the next step docking studies will be performed to generate binding affinities. This investigation is expected to reveal some compounds with affinities higher than SirReal2. Extended ADME analysis will be employed further to strengthen the fact that these drug like commercial compounds from ZINC database will display greater viability for advancement in the pharmacological field. In contrast with the previous studies on this matter, these probable inhibitors will be shown to be capable of crossing the blood brain barrier making them a better choice. Such analysis of compounds can significantly reduce the time and cost of wet lab research. Conclusively, results from this study will strongly advocate for the analysis of these probable inhibitors inside living systems. Result: During the course of our study, out of the initial 400 similar compounds, ADME analysis left us with 79 compounds which were all BBB permeable. Docking analysis of these compounds identified seven with binding affinities higher than the reference, SirReal2 (-10.8 kcal/mol). with the highest affinity at -11.4 kcal/mol. Conclusion: Among the seven identified compounds, Compound 7 emerged as the most effective, with the highest binding affinity and being BBB permeable. We recommend validating these findings through in vivo experiments.