Multiscale Computational Modeling for understanding the interaction between Pt(II)-NHC complexes and DNA

This study investigates the interaction of Pt(II)-NHC complexes, potential antitumor alternatives to cisplatin, with DNA using a multiscale computational approach. "Blind" molecular docking (MetalDock program) against DNA (PDB 1BNA) identified the minor groove as the preferred binding site, with affinities between -6.72 and -8.23 kcal/mol. The presence of methoxy groups favored the affinity between the complexes and the nitrogenous bases of DNA. Binding affinity showed a strong correlation with HOMO energy (r = -0.93), but not with the cytotoxicity of the complexes (r = 0.25), expressed as pIC₅₀. The covalent bonding step was investigated using DFT calculations employing the BLYP-D3(BJ)/LANL2TZ(f)/def2-SVP/CPCM protocol (ORCA 6.1 program), revealing an endergonic aquation followed by an exergonic substitution, with a preference for guanine over adenine, similar to that observed for cisplatin. The experimental chemical shifts of ¹⁹⁵Pt showed the strongest correlation with activity (r = 0.86), and methodologies for their theoretical prediction will be proposed.