Exploración de los sitios de unión de antitumorales a la tubulina mediante herramientas computacionales y simulaciones de dinámica molecular

Abstract

Cancer, in its many forms, is one of the main diseases of our time and, according to the World Health Organization, one of the major causes of premature death in industrialized countries. The pharmaceutical armamentarium to treat malignancies includes agents that interfere with DNA biosynthesis and others that alter the cellular machinery necessary for cell division. Among the therapeutic families that compose this last group one of the most extended in clinical use is the family of microtubule interfering drugs, initially represented by the Vinca alkaloids and then extended with the incorporation of paclitaxel, which was isolated from the bark of the Pacific yew tree. Nonetheless more efforts are needed aimed at obtaining new chemical entities capable of binding to microtubules with high affinity and simultaneously overcoming the described resistances to treatment. Computational methods have become increasingly useful in a number of areas such as characterization of ligand-binding sites, ligand docking and molecular dynamics simulations as they provide information that is usually beyond experimental possibilities. The purpose of this D. Phil. thesis was to study, by means of molecular modelling techniques and computational methods, the binding of microtubule stabilizing and destabilizing drugs to their different target sites in tubulin and gain additional insight into the structure-activity relationships. This research was carried out in collaboration with the groups of Profs. Fernando Díaz and José Manuel Andreu at the Centro de Investigaciones Biológicas (CSIC), Prof. Weishuo Fang’s group at the Institute of Materia Medica of the Chinese Academy of Medical Sciences, Dr. Antonio Morreale’s group at the Centro de Biología Molecular Severo Ochoa (CSIC), and PharmaMar researchers.