Substitution-inert polynuclear platinum complexes and Glycosaminoglycans: A molecular dynamics study of its non-covalent interactions

An impressive class of formally substitution-inert polynuclear platinum complexes known as Substitution-inert Polynuclear Platinum (II) Complexes (SI-PPCs) present an attractive approach for medicinal inorganic chemistry through high-affinity non-covalent interactions with biomolecules, such as DNA and Glycosaminoglycans (GAGs). This interaction occurs through the formation of non-covalent cyclic structures called clamps and forks with the phosphate and sulfate groups present in these biomolecules. This work shows several analyses of the non-covalent interactions formed between heparin (PDB code: 1HPN) and SI-PPCs obtained through molecular dynamics (MD) simulations. Root Mean Square Deviation (RMSD) results showed that the “non-covalent” di-nuclear platinum compound, DiplatinNC ([{trans-Pt(NH3)2(NH2(CH2)6NH3+)}2-μ-NH2(CH2)6NH2]6+) and AH44 ([{Pt(NH3)3}2{(μ-(H2N(CH2)6NH2)2-(trans-Pt(NH3)2}]6+, 0,0,0/t,t,t,) complexes, which are both 6+ charged complexes, were the most rigid. On the other hand, the Root Mean Square Fluctuation (RMSF) showed that there is a reduction in the atomic fluctuation of atoms in the central region of the heparin molecule; the solvent accessible surface area (SASA) analysis also indicates a reduction in the accessible area by the heparin when interacting with SI-PPCs. The evaluation of H-Bond data confirms the formation of the non-covalent interactions, which may suggest a decrease in the action of 1HPN by preventing the action of enzymes on this substrate. In addition, thermodynamic results indicate that this interaction is spontaneous, considering the negative variations in the Gibbs free energy presented by the studied systems. Substitution-inert Polynuclear Platinum (II) Complexes interact with the heparin model, 1HPN, resulting in metalloshield and modulation of biological function to inhibit the metastasis process. [Display omitted] •Platinum (II) centers preferentially bind to sulfate groups generating changes in heparin.•Molecular dynamics closely analyzes interactions for a full depict of ligand trajectories.•Analysis of H-bonds proof the formation of non-covalent structures.•Triplatin complexes exhibited the highest number of native contacts and H-Bonds.•Metalloshield and modulation of biological function inhibit the metastasis process.