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