Computational evaluation of a panel of combretastatin compounds as warheads for PROTAC design targeting β tubulin isoforms.

A new strategy for chemotherapy-based therapy of various types of cancer is based on the design of PROTAC molecules, which are hybrid chemical structures aiming to degrade over-expressed proteins via ubiquitination pathways in cancer cells. They consist of a warhead that binds to an overexpressed protein marked for degradation, a linker and a compound that binds to an E3 ligase enzyme. A panel of recently synthesized combretastatin derivatives with attractive pharmacological properties have been investigated in this project. They were docked to the main β tubulin isotypes and their binding affinities were compared. The ADMET properties of these compounds were analyzed and used to search for a correlation with the biological activity of these derivatives, which were previously tested in vitro to assess their cytotoxicity. The best linear correlation was observed between the binding energy obtained by docking and the IC50 obtained experimentally. In a cell, all isotypes of β tubulin are present simultaneously, with different expression levels depending on tissue type and whether the tissue is cancerous or healthy. To carry out the regressions, an attempt was made to estimate the binding energy weighted on the isotypes expressed in that specific cell line. Models were created for seven cancer cell lines whose experimental results had been provided. None of these compounds seems to exhibit selectivity for a specific isotype. The two best compounds were chosen based on the results of the experimental assays and were evaluated as possible warheads for a PROTAC structure that aims to bind all β tubulin isotypes indiscriminately, thus as a general antimitotic drug.