Exploration of anticancer potential of hydroxamate derivatives as selective HDAC8 inhibitors using integrated structure and ligand based molecular modeling approach

Abstract

Recently, histone deacetylase inhibitors are evolving as an exhilarating new class of promising antitumor agents for the treatment of multiple malignancies. It may play a pivotal role as a therapeutic target for challenging the globally wide spread disease, cancer. At the same time, the prediction of biological activity of novel compounds, which was once a major challenge in drug design, is also pacing up its speed. This computational study has been performed in Schrodinger suite packages such as sitemap generation, grid formation, Glide for docking, Quikprop for ADME analysis, e-pharmacophore post docking script and Phase for 3D QSAR models designing, that all are available in Maestro version 9.3. Docking not only helps in predicting the preferred orientation of ligand with its target receptor, but also the binding affinity between the ligand and receptor. The application of Phase and e-pharmacophore script predicts some computational models of the provided ligands using 3D QSAR method. This decreases the cost and time of biological experiments. Glide XP reveals that compound 21 with the highest score value as the best compound from the dataset. Also, it shows good R²=0.9834,
Q²= 0.7753, stability = 0.5407 and low standard of deviation SD=0.1085 for hypothesis ADDRR.1601, for the PLS factor 5. The outcome of these studies suggests compound 21 as a potential drug molecule for HDAC targets.