Common SAR Derived from Multiple QSAR Models on Vorinostat Derivatives Targeting HDACs in Tumor Treatment.

BACKGROUND: Dysregulation of HDACs has been associated with tumour development and therefore inhibiting HDAC's have surfaced as promising therapeutic strategy in malignancy. METHODS: Vorinostat analogues with different biological activities were investigated for underlying structure-activity relationship. RESULTS: Out of six activities and their multiple QSAR models, HDAC1 and HDAC8 produced statistically fit, stable and predictive linear (MLR) and non-linear (SVM) QSAR models. In case of HDAC1 activity as end point, linear (R2=0.8089, R2 CV=0.7343) and non-linear (R2=0.9801, R2 CV=0.8952) QSAR models turned reliable to investigate SAR. Similarly, HDAC8 activity based linear (R2=0.9454, R2 CV=0.9049) and non-linear (R2=0.9899, R2 CV=0.9232) QSAR models produced statistically improved and stable models. CONCLUSION: Molecular descriptors derived from 3-D Morse and Radial Distribution Function indices were found to be selective in all the models. These molecular descriptors which encode common SAR among Vorinostat derivatives were evaluated for their potent HDAC inhibition activity.

Pharmacological Analysis of Vorinostat Analogues as Potential Anti-tumor Agents Targeting Human Histone Deacetylases: an Epigenetic Treatment Stratagem for Cancers.

Alteration of the acetylation status of chromatin and other non-histone proteins by HDAC inhibitors has evolved as an excellent epigenetic strategy in treatment of cancers. The present study was sought to identify compounds with positive pharmacological profiles targeting HDAC1. Analogues of Vorinostat synthesized by Cai et al, 2015 formed the test compounds for the present pharmacological evaluation. Hydroxamte analogue 6H showed superior pharmacological profile in comparison to all the compounds in the analogue dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify compounds with even better high affinity and pharmacological profile than 6H and Vorinostat, virtual screening was performed. A total of 83 compounds similar to Vorinostat and 154 compounds akin to analogue 6H were retrieved. SCHEMBL15675695 (PubCid: 15739209) and AKOS019005527 (PubCid: 80442147) similar to Vorinostat and 6H, were the best docked compounds among the virtually screened compounds. However, in spite of having good affinity, none of the virtually screened compounds had better affinity than that of 6H. In addition SCHEMBL15675695 was predicted to be a carcinogen while AKOS019005527 is Ames toxic. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report Vorinostat hydroxamate analogue 6H to be a potential candidate for HDAC inhibition in treatment of cancers through an epigenetic strategy.