3D QSAR of Aminophenyl Benzamide Derivatives as Histone Deacetylase Inhibitors

Mahipal; Om      Prakash Tanwar; C.      Karthikeyan; N.      S. Hari Narayana Moorthy; Piyush      Trivedi

Abstract

The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 48 aminophenyl benzamide derivatives reported for Histone Deacetylase (HDAC) inhibition using PHASE module of Schrodinger software. A five point pharmacophore model consisting of two aromatic rings (R), two hydrogen bond donors (D) and one hydrogen bond acceptor (A) with discrete geometries as pharmacophoric features was developed and the generated pharmacophore model was used to derive a predictive atom-based 3D QSAR model for the studied dataset. The obtained 3D QSAR model has an excellent correlation coefficient value (r2=0.99) along with good statistical significance as shown by high Fisher ratio (F=631.80). The model also exhibits good predictive power confirmed by the high value of cross validated correlation coefficient (q2 = 0.85). The QSAR model suggests that hydrophobic character is crucial for the HDAC inhibitory activity exhibited by these compounds and inclusion of hydrophobic substituents will enhance the HDAC inhibition. In addition to the hydrophobic character, hydrogen bond donating groups positively contributes to the HDAC inhibition whereas electron withdrawing groups has a negative influence in HDAC inhibitory potency. The findings of the QSAR study provide a set of guidelines for designing compounds with better HDAC inhibitory potency.

Keywords: Aminophenyl benzamide, Histone deacetylases inhibitors, Pharmacophore, PHASE, QSAR, Schrodinger

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