What is it about?
Supramolecular contacts responsible for the mechanism of action of epothilone A chemotherapeutic drug in the taxane pocket of the β-tubulin are addressed, combining quantum theory of atoms in molecules with density functional theory. We also derive the conformational shaping and the electronic eigenstates involved in photopharmacology experiments of CouEpo—a photocaged epothilone microtubule-stabilizing agent—in A549 cell lines.
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Photo by National Cancer Institute on Unsplash
Why is it important?
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.
Perspectives
The results that have emerged highlight the cooperative role that non covalent interactions play in stabilizing the observed T2R-TTL-EpoA host:guest crystallographic complex from the Bos taurus organism. More specifically, QTAIM descriptors from DFT converged electronic wavefunctions in a dielectric medium are applied with the target of characterizing the H-bonding contacts of EpoA with atoms of residues Asp226, Thr276, and Gln281 from the crystallographic structure. Also, we clearly identify the CouEpo perturbed electronic degrees of freedom responsible for the peculiar band at almost 400 nm and responsive during photopharmacology experiments with visible light within A549 cells. It should also be mentioned that we present data dealing with the QM charge distribution of the CouEpo molecule in water, indicating its local properties finely modulating interactions with surrounding molecules/residues in terms of electrophilic or nucleophilic reactivity. In addition, from finite-temperature MD simulations, it was revealed that under equilibrium conditions in water solution, the CouEpo modulates its conformational shaping, fluctuating between folded (or partially folded) and elongated conformations over a nanosecond time scale dynamics. Given the complexity of the systems investigated, we believe that the present research study, while combining different simulation techniques, might contextually contribute to the literature on epothilone compounds with specific information from quantum and classical mechanics, useful to provide some insights on this intriguing family of anticancer drugs.
Dr Costantino Zazza
Universita degli Studi della Tuscia
Read the Original
This page is a summary of: High‐Performance Epothilone‐Based Microtubule Stabilizers as Anticancer Agents: Insights from DFT/QTAIM/MD Computational Modeling, ChemistrySelect, August 2025, Wiley,
DOI: 10.1002/slct.202502546.
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