Microtubule targeting agents: A bridge between Paclitaxel and Microtubules lateral contacts

Microtubules (MT) are small cellular components that play a fundamental role in development, proliferation, spreading, and signaling of cells. The basic lattice of MTs is composed by the alternation of α and β protein subunits called tubulins. Over the decades, they have become the main target of drugs involved in the treatment against tumors. Chemotherapy drugs can be divided into two main categories: stabilizing and destabilizing agents, which, according to their properties, can stabilize or destabilize the lattice of MTs, leading to cell apoptosis. This is the case of Paclitaxel (PTX), a prominent chemotherapy drug used in breast cancer treatment. It aims to stabilize MTs through the firming of longitudinal and lateral contacts. Even though PTX is one of the most powerful and useful drugs used nowadays, often there are cases of resistance towards this compound. Several reasons have been suggested to understand how this mechanism developed. Surely, mutations in the amino acid sequences in β tubulin isotypes can affect the way PTX binds to its luminal site, leading to an incorrect stabilization of MTs. In the following study, different mutations of β tubulin isotypes will be analyzed and how the latter could affect the lateral contacts between adjacent α and β subunits. Through computational techniques, including molecular dynamics simulations and docking studies, it will be delineated how mutations in β tubulin isotypes can influence PTX's binding affinity to its target site, consequently affecting its ability to stabilize MTs. In conclusion, the aim of the project will be to better understand the mechanisms of ligand-receptor interaction, even in the presence of mutations, to make chemotherapy treatments increasingly precise and reliable.