Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin’s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis.