Molecular Docking Supplements an In vitro Determination of the Leading CYP Isoform for Arylpiperazine Derivatives.

Background: Molecular docking has often been used before to calculate in silico affinity of drugs towards their molecular target, but not to estimate leading CYP isoform responsible for metabolism of studied compounds.

Objective: The aim of this study is to present molecular docking as a valid alternative for costly in vitro studies resulting in estimation of leading CYP isoform.

Methods: In vitro part was based on incubations of studied compounds with isolated CYP3A4 isoform followed by LC-MS analysis. The in silico stage consisted of docking three-dimensional models of the studied compounds with a three-dimensional model of the leading metabolizing isoform (CYP3A4), which was designated during the in vitro part of the study. XenoSite P450 metabolism prediction was also used to predict sites of metabolism and calculate probability values.

Results: The calculated affinities showed a clear similarity when the in vitro results were compared with the calculated in silico affinity values. XenoSite CYP3A4 metabolism probability values also confirm significant participation of CYP3A4 in metabolism of studied compounds.

Conclusion: Both molecular docking and XenoSite P450 metabolism prediction provide data that stands in agreement with in vitro studies, granting a more detailed spectrum on predicting CYP3A4 metabolism, and presenting molecular docking as a promising tool to cut costs and increase effectiveness in early drug development stages.