Exploration of Fingerprints and Data Mining-based Prediction of Some Bioactive Compounds from Allium sativum as Histone Deacetylase 9 (HDAC9) Inhibitors.

Background: Histone deacetylase 9 (HDAC9) is an important member of the class IIa family of histone deacetylases. It is well established that over-expression of HDAC9 causes various types of cancers including gastric cancer, breast cancer, ovarian cancer, liver cancer, lung cancer, lymphoblastic leukaemia, etc. The important role of HDAC9 is also recognized in the development of bone, cardiac muscles, and innate immunity. Thus, it will be beneficial to find out the important structural attributes of HDAC9 inhibitors for developing selective HDAC9 inhibitors with higher potency.

Methods: The classification QSAR-based methods namely Bayesian classification and recursive partitioning method were applied to a dataset consisting of HADC9 inhibitors. The structural features strongly suggested that sulphur-containing compounds can be a good choice for HDAC9 inhibition. For this reason, these models were applied further to screen some natural compounds from Allium sativum. The screened compounds were further accessed for the ADME properties and docked in the homology-modelled structure of HDAC9 in order to find important amino acids for the interaction. The best-docked compound was considered for molecular dynamics (MD) simulation study.

Results: The classification models have identified good and bad fingerprints for HDAC9 inhibition. The screened compounds like ajoene, 1,2 vinyl dithiine, diallyl disulphide and diallyl trisulphide had been identified as compounds having potent HDAC9 inhibitory activity. The results from ADME and molecular docking study of these compounds show the binding interaction inside the active site of the HDAC9. The best-docked compound ajoene shows satisfactory results in terms of different validation parameters of MD simulation study.

Conclusion: This in-silico modelling study has identified the natural potential lead (s) from Allium sativum. Specifically, the ajoene with the best in-silico features can be considered for further in-vitro and in-vivo investigation to establish as potential HDAC9 inhibitors.