Emprego de complexos de vanádio para manipular a autofagia: cálculos quânticos e desenvolvimento de parâmetros de campo de força

Abstract

The modulation of autophagy has been presented as a very useful strategy in anticancer treatments. In this sense, it is known that vanadium complexes (VCs) are capable of both inhibiting and inducing autophagy in cancer cells. In this work, two vanadium complexes were used. The first compound, [VO(oda)(phen)], has proven efficiency in inhibiting autophagy in pancreatic cancer cells. The second, [VO(bpy)2Cl], is known for having the ability to induce autophagy in triple-negative breast cancer cells. In this context, Molecular Dynamics (MD) simulations are excellent strategies to investigate the interaction between metallic complexes and their biological targets. However, simulations of this type are heavily dependent on the proper choice of the force field (FF). General FFs are not efficient to describe the properties of metallic complexes. Furthermore, specific FFs for the VCs targeted by this study have not yet been reported in the literature. That way, this thesis presents an investigation divided into three parts: development, validation, and application. Therefore, initially it is proposed the development of AMBER FF parameters for the two VCs, from a minimum energy structure, obtained by DFT calculations using B3LYP/def2-TZVP level of theory plus ECP for the vanadium atom. From the optimized geometry, the calculations of the Hessian matrix and the RESP charges were performed to provide the charges of each atom, the force constants and the equilibrium values. Lennard-Jones parameters for all atoms except vanadium were assigned according to GAFF. Vacuum MD simulations were performed to validate the developed FFs. Structural analyses allowed to find values with appreciable agreements between the experimental data and the quantum reference. From the developed and validated FFs, it was possible to investigate the interactions between the VCs and the PI3K and ULK1 proteins, crucial for the autophagic machinery. RMSD, hydrogen bonds, and RMSF analyses were performed. In addition, we present how the VCs act to inhibit/induce autophagy and suggest how it would be possible to modify the actions of the complexes so that autophagy modulation occurs. From a general perspective, our findings encourage new parameterizations of metallic complexes with significant biological importance, as well as allow to contribute to the elucidation of the complex process of autophagy.