Use of Volsurf approach for pharmacokinetic optimization of β-carboline derivatives as antitumor agents

The β-carboline derivatives are a large group of naturally-occurring and synthetic alkaloids which have a wide spectrum of biological and pharmaceutical properties. The newly developed procedure called VolSurf has been used to explore a significant correlation between the 3D molecular interaction fields (MIF) and physicochemical and pharmacokinetic properties of a set of 30 β-carboline compounds acting as antitumor agents. In general terms, VolSurf generates a limited set of quantitative numerical descriptors from MIFs by calculating the volume or the surface of the interaction contours. These descriptors that encode the information content from the chosen probes are simple to interpret from a chemistry point of view. The aim of this approach is to allow the analysis of a large number of quantitative descriptors by using chemometric tools such as partial least squares (PLS) and principle component analysis (PCA). The PLS model gave statistically significant results with R2 and Q2 values of 0.92 and 0.72, respectively. The ability of the model was validated by an external test set of 10 compounds, which gave R2 (pred) of 0.85. The VolSurf model developed here identifies hydrophobicity as the major physicochemical parameters responsible for the antitumor activity of the β-carboline derivatives towards HepG2 cell lines.