Molecular docking, ADME/Tox prediction, and in vitro study of the cell growth inhibitory activity of five β-carboline alkaloids

In a continuing effort to find new cytotoxic, antitumor, and less toxic agents from β-carbolines derivatives, using experimental and computational studies, five β-carboline alkaloids were tested in vitro for their cell growth inhibitory activity using Lepidium sativum phytotest. Then, molecular docking and correlation analysis between activity and structure study was performed to identify the interaction mode between these compounds and the colchicine binding site of tubulin. The experimental results revealed that harmaline and harmalol represent the most active compounds with IC 50 of 134.15 μg/mL and 239.43 μg/mL, respectively, lower than colchicine which is 248 μg/mL. The correlation analysis between activity and structure indicates that the hydroxy group and the partial hydrogenation of the pyridyl ring increase activity. Indeed, molecular docking analysis revealed that harmaline and harmalol have low binding energy and could interact, in particular through conventional hydrogen bonds and van der Waals interactions with the colchicine binding site of tubulin, indicating that harmaline and harmalol could have an antimitotic effect. Moreover, in silico analysis of ADME/Tox properties reveals that these molecules possess promising pharmacokinetic properties in terms of intestinal adsorption, volume of distribution, blood-brain barrier permeability and toxicity. The results obtained were used to design new harmaline derivative molecule, with promising results after a preliminary in silico evaluation. In summary, our results indicate that the β-carboline alkaloids studied have an in vitro and in silico antimitotic activity and their pharmacokinetic properties are promising and should be confirmed by an in vivo study.