Pharmacophore Development and Docking Studies of the HIV‐1 Integrase Inhibitors Derived from N‐methylpyrimidones, Dihydroxypyrimidines, and Bicyclic Pyrimidinones

Abstract

To elucidate the crucial structural features for the HIV-1 integrase inhibitors, a three-dimensional pharmacophore model was developed based on N-methyl pyrimidones, dihydroxypyrimidines, and bicyclic pyrimidinones derivatives using Phase. N-methyl pyrimidone derivative raltegravir, the first US-FDA approved drug by Merck, belongs to this series. The best-fitted common pharmacophore hypothesis was characterized by two acceptor, two hydrophobic, and two ring features having a correlation coefficient of 0.895, cross-validated Q(2) value of 0.631, and survival score of 8.862, suggesting that a highly predictive pharmacophore model was developed. The cross-validation studies using 23 test set molecules and fifteen structurally diverse HIV-integrase inhibitors give extra confidence about the correctness of the pharmacophore model. The cross-validation studies proved that our developed model can successfully differentiate between active and inactive HIV-integrase inhibitors. The docking studies were also carried out wherein the molecules were docked against the active site of HIV integrase to analyze the binding mode and the necessary structural requirement for their respective enzymatic inhibition. The results obtained from our studies provide a valuable tool for designing of new lead molecules with potent activity.