Simulation of the interaction mechanisms of the outer surface of albumin with platinum(II) complexes

The development of new approaches for evaluating the interaction of chemotherapeutic drugs with blood proteins is one of the key areas of modern research aimed at improving the effectiveness of anticancer therapy. The mechanisms of binding these drugs to proteins, as well as their impact on the spatial structure of protein molecules, remain insufficiently studied. Platinum-based drugs, particularly cisplatin and carboplatin, are widely used in chemotherapy for cancer treatment. Their primary mechanism of action involves interaction with the DNA of tumor cells, leading to disruption of cellular functions and triggering apoptosis. However, studying their interactions with blood proteins is equally important, as these processes can significantly influence the pharmacokinetics of the drugs - their bioavailability, tissue distribution, and toxicity levels. This study employs quantum chemical modeling to elucsdate the interaction mechanisms of platinum(II) complexes: cisplatin and carboplatin with amino acids characteristic of the hydrophilic domain of human serum albumin, a major protein component of human blood. The modeling was conducted using quantum chemistry method. The formation of stable intermolecular complexes between Pt?? ions and amino acid residues: arginine, glutamine, serine, aspartic acid, cysteine, and lysine was elucidated. Various types of interactions (hydrogen bonding, coordination, and electrostatic) were analyzed and the interaction energies for each complex were calculated. Glutamine and arginine residues showed the highest affinity for Pt??, forming the most energetically favorable complexes with both drugs. Carboplatin demonstrated greater thermodynamic stability in interactions with all studied amino acids compared to cisplatin, which is attributed to the presence of oxygen-containing functional groups in its molecular structure. These findings indicate a higher propensity of carboplatin to bind to plasma proteins, which may partially explain its lower toxicity compared to cisplatin under equivalent dosing conditions.