Binding interaction between human serum albumin and cisplatin analogs substituted with different amine ligands: multi-spectroscopic investigation, molecular docking, and molecular dynamics simulations.

Human serum albumin plays an essential role in the bioavailability and transition of metal-based anticancer drugs. In this study, the binding interaction of human serum albumin with three cisplatin-substituted analogs was investigated. The Pt (II) complexes with the formula cis-[Pt (R-NH2)Cl2], where R is methyl, propyl-, and butyl-alkyl groups, were synthesized and structurally characterized by analyzing computational and experimental results. Their cytotoxic behavior was tested against human breast adenocarcinoma (MCF7) and colorectal carcinoma (HCT116) cell lines. According to these findings, IC50 values of methyl derivative (35 and 28 μM)) are near cisplatin (30.5 and 15 μM) against both MCF7 and HCT116 cell lines, respectively. To predict the reactivity in protein interaction and structure-activity relationship in all these cisplatin derivative systems, density functional theory was used. The binding modes and the affinities in HSA interaction were investigated through a range of methods, including electronic absorption, fluorescence, circular dichroism scanning, computational molecular docking modeling, and molecular dynamics simulation. The study found that these compounds could bind (with a similar affinity to cisplatin for the methyl derivative in HSA unfolding) and interact with HSA via hydrogen bonds and hydrophobic interactions. Experimental binding data were in agreement with the results predicted using docking simulation. The findings indicated that among three Pt agents, the methyl derivative had the greatest negative docking energy (-8.13 kcal/mol) and the highest affinity in HSA interaction, similar to cisplatin (-8.93 kcal/mol). Molecular dynamics simulations revealed favorable binding of cis-[Pt (NH3)2Cl2] and cis-[Pt (methyl-NH2)2Cl2] to human serum albumin. The methyl-substituted complex showed higher flexibility and reduced stability. MM-PBSA analysis confirmed strong thermodynamic interactions, mainly governed by hydrophobic and van der Waals forces, with minimal hydrogen bonding contribution.