High‐Performance Epothilone‐Based Microtubule Stabilizers as Anticancer Agents: Insights from DFT/QTAIM/MD Computational Modeling

Abstract Epothilone‐based molecular agents are known to promote microtubule (MTs) assembly and stability and are commonly used for clinical studies in several cancer pathologies. For this reason, epothilones and derivatives have been largely studied in the last decades as MT‐targeting agents. Here we finely address, combining quantum theory of atoms in molecules (QTAIM) with density functional theory (DFT), supramolecular contacts driving the complexation of epothilone A, EpoA , within β‐tubulin on the deposited crystallographic structure (PDB:4I50) from Bos taurus organism. The crystallographic structure is taken as a reference condition for proposing the first theoretical study of a recently released photocaged epothilone microtubule‐stabilizing reagent, called CouEpo , featuring temporal resolution control of MTs and relative dynamics in A549 cell lines. In this study, we also report an accurate description of CouEpo electrostatic potential surface (ESP) as well as of the electronic degrees of freedom that finely modulate the adsorption of light during photopharmacology applications. UV/vis spectroscopic properties are also compared with those arising from EpoA and Sagopilone ( ZK‐Epo ) in the framework of the time‐dependent density functional theory (TD‐DFT). Finally, we realize that the CouEpo agent shows a sort of folding/unfolding conformational equilibrium in aqueous solution, mainly driven by thermal fluctuations and intramolecular noncovalent interactions.