1,3,5-Triazine Based Hydroxamic Acid Analogues as HDAC Inhibitors: Integrated Modelling by 3D QSAR, Hypogen Pharmacophore Based Virtual Screening and Molecular Dynamic Simulation Studies

Abstract

Abstract Histone deacetylase (HDAC) is one of the therapeutically relevant target for the treatment of various types of cancer. To establish a correlation between biological potency and their structural features using a combined approach of Hypogen pharmacophore and five different 3D QSAR models. Hypogen model (Hypo1) for HDAC inhibitors was developed on the basis of existing one, having good correlation coefficient (R= 0.76), lowest root mean square deviation (RMSD) of 0.91, maximum fit value of 9.77 and highest cost difference value of 66.86. Quality validation of Hypo1 through cost analyses, test set prediction and Fischer’s randomization test suggested that the model can reliably detect HDAC inhibitors. The five different 3D QSAR models i.e., Recursive Partitioning Classification Model (pkRP model), Multiple Linear Regression (MLR) analysis, Partial Least Square (PLS), Genetic Function Approximation (GFA) models and Field based (or Grid Based) QSAR models were created and validated. Furthermore, top scored compounds were filtered through the virtual screening and after that, molecular dynamic (MD) simulation and MM-GBSA studies were used to validate the stability, binding energy and electrostatics of best HDAC receptor-ligand complex. The outcome of findings indicated that the best Field based model has R2=0.970and Q2=0.842, the best pkRP model has R2= 0.883 and Q2= 0.813, the best PLS model has R2= 0.856 and Q2= 0.746,the best MLR model has R2= 0.766 and Q2= 0.752, and the best GFA model has R2= 0.706 and Q2= 0.663. Cross-validated coefficient, (rcv2) of 0.968, 0.827, 0.743, 0.810 and 0.552 was found for Field/Grid based, pkRP, MLR, PLS and GFA model, respectively indicating the satisfied correlativity and prediction. The outcome of these studies will be a focal paradigm for designing of novel lead molecules as HDAC inhibitors with improved anticancer activity.