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

Abstract

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