Development and biological application of a quantum mechanically derived force field: the case of a platinum (II) complex

Abstract

The metals exhibit a great chemical and biological diversity, and their use in medicine was increased with the discovery of the antitumor activity of cisplatin ([Pt (NH3) (Cl)]). Since then, several Platinum-based (Pt) compounds have been developed, but only two of them (Carboplatin and Oxaliplatin) have received approval for worldwide use by the Food and Drug Administration (FDA). In this context, the use of computational tools plays an important role in the design of new drugs and predicting their properties. One methodology that allows the simulation of new drugs under in vivo conditions is the classical Molecular Dynamics (MD). However, adopting a model that adequately describes the molecular system in the simulation is critical. Nevertheless, for the description of metallodrugs and/or very conjugated molecules the parameters already available in the literature are generally scarce or may not be reliable. In this sense, a new set of AMBER force field parameters, based on density functional theory (DFT) calculations, has been developed, validated and applied to a possible anticancer platinum (II) complex (cis-dichloro(2-aminomethylpyridine)platinum (II) bonded to 2- (4'-amino2'-hydroxyphenyl)benzothiazole (AHBT)). In order to clarify some disagreements in the literature about the existence or not of a chemical bond between the Pt complex and DNA, the developed model was applied in two MD simulations: Pt complex bonded to the DNA and a non-bonded system. The parameterization validation shows that the new model adequately describes the structural properties of the complex, being in very good agreement with the quantum reference structure. In addition, the simulation results reveal a high affinity between the DNA minor groove and the studied metallic complex. When coordinated, it induces conformational changes in the DNA structure. Overall, we expect this work to contribute significantly to future MD simulations of Pt complexes in biological targets, still not well explored mainly due to the few metal parameters for found in the literature.