Pharmacophore Mapping and Virtual Screening for SIRT1 Activators

Bulletin of the Korean chemical society

Keun Woo Lee¹  Hyong Ha Kim¹  Sugunadevi Sakkiah¹  Poornima Gajendrarao¹  Songmi Kim¹  Jung Keun Suh¹  Yuno Lee¹  Navaneethakrishnan Krishnamoorthy¹  Sundarapandian Thangapandian¹ 

关键词: Sirtuin;    Sirtuin Activator;    Pharmacophore;    HipHop;    SIRT1;   

DOI  :  

学科分类：化学（综合）

来源: Korean Chemical Society

【 摘 要 】

Silent information regulator 2 (Sir2) or sirtuins are NAD(+)-dependent deacetylases, which hydrolyze the acetyllysine residues. In mammals, sirtuins are classified into seven different classes (SIRT1-7). SIRT1 was reported to be involved in age related disorders like obesity, metabolic syndrome, type II diabetes mellitus and Parkinson’s disease. Activation of SIRT1 is one of the promising approaches to treat these age related diseases. In this study, we have used HipHop module of CATALYST to identify a series of pharmacophore models to screen SIRT1 enhancing molecules. Three molecules from Sirtris Pharmaceuticals were selected as training set and 607 sirtuin activator molecules were used as test set. Five different hypotheses were developed and then validated using the training set and the test set. The results showed that the best pharmacophore model has four features, ring aromatic, positive ionization and two hydrogen-bond acceptors. The best hypothesis from our study, Hypo2, screened high number of active molecules from the test set. Thus, we suggest that this four feature pharmacophore model could be helpful to screen novel SIRT1 activator molecules. Hypo2-virtual screening against Maybridge database reveals seven molecules, which contains all the critical features. Moreover, two new scaffolds were identified from this study. These scaffolds may be a potent lead for the SIRT1 activation.

【 授权许可】

Unknown