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

Authors

Chemistry Department, Faculty of Science, K.N. Toosi University of Technology, Tehran, Iran

Abstract

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.

Keywords


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