Resumo:
Cisplatin (cis-[Pt(NH3)2(Cl)2]) is known to be an important agent in the fight against
various types of cancer, acting on DNA and resulting in distortions in the
macromolecular structure that induce the cell to programmed death. With the frequent
use of cisplatin, the response of cells is the induction of drug resistance mechanisms,
complicating treatment. Numerous studies indicate that cells can absorb and transport
cisplatin through the ATP7A and ATP7B transport proteins, which are responsible for
the regulation of Cu(I). These proteins are also related to the mechanisms of cellular
resistance to the drug due to the intensified flow of cisplatin to the extracellular medium.
In this work, DFT calculations with the M06-2X functional and NCI for investigating
non-covalent interactions were used throughout mechanistic proposals for the
reactions of cis-[Pt(NH3)2(Cl)2] and cis-[Pt(NH3)2(OH2)2]2+ with the active site of the 6th
metal-binding domain (Mnk6) of the ATP7A protein, both in the presence and absence
of Cu(I) in the protein structure, and in both gas phase and implicit solvation. The
results indicated the existence of distinct stages with associative characteristics. In the
gas phase, the reaction coordinates suggest greater thermodynamic and kinetic
favorability for the diaquo reagent compared to the dichloro; and for the holoprotein
form compared to the apoprotein. In the solvated medium, however, the reactions
between the diaquo and dichloro forms with the holoprotein site showed barrier
energies and free energy changes for the reaction that were remarkably close in the
first stage (around 12.3 kcal·mol-1 and 12.0 kcal·mol-1, respectively). In the holoprotein
forms, strongly attractive interactions of Cu(I) with Pt(II) were observed, which may
impact the reaction rate and stabilization of reagent complexes. Through topological
analyses and other observations, the hypothesis is that these are non-covalent
interactions, exhibiting in several cases electronic densities greater than those
observed for typical hydrogen bonds. NBO calculations also indicated possible charge
transfers from S and Cu(I) to Pt(II), concurrently with changes in geometries
concerning the metal centers. However, the structural cut of the protein (i.e., the active
site) and the failure to obtain IRC results under certain transition states may be
considered limiting factors.
