Combining ligand-based and structure-based drug design approaches to study the structure-activity relationships of a -carboline derivative series

In this study, we investigated the structure-activity relationships of a series of -carboline alkaloid derivatives using the 2D-QSAR and molecular docking, in order to identify the mode of interaction between -carboline derivatives and the PLK1 kinase, and determine their key substituents responsible for the cytotoxic activity. The obtained QSAR models using multiple linear regression (MLR) and partial least squares (PLS) methods showed a high correlation between the experimental activity and the predicted one by PLS (R-PLS(2)=0.82, q(2)=0.72) and MLR (R-MLR(2)=0.82, q(2)=0.72). An external dataset was used to test the extrapolation power of the models which resulted in an R-PLS(2) (EV)=0.76; RMSE=0.39. The 2D-QSAR analysis reveals that lipophilicity plays an important role in the cytotoxic activity of this group of -carboline derivatives. Indeed, the molecular docking study into the active site of the polo-like kinase (PLK1) revealed that the most active ligand 57 shows higher binding energy and interacts, especially by H-bonds and hydrophobic interactions, with the active site of the PLK1 kinase. Consequently, the results obtained from the 2D-QSAR and docking studies provided a useful tool to design new and potent -carboline derivatives as cytotoxic agents.