Validation and Applications of Protein–Ligand Docking Approaches Improved for Metalloligands with Multiple Vacant Sites

Decoding the interaction between coordination compounds and proteins is of fundamental importance in biology, pharmacy, and medicine. In this context, protein–ligand docking represents a particularly interesting asset to predict how small compounds could interact with biomolecules, but to date, very little information is available to adapt these methodologies to metal-containing ligands. Here, we assessed the predictive capability of a metal-compatible parameter set for the docking program GOLD for metalloligands with multiple vacant sites and different geometries. The study first presents a benchmark of 25 well-characterized X-ray metalloligand–protein adducts. In 100% of the cases, the docking solutions are superimposable to the X-ray determination, and in 92% the value of the root-mean-square deviation between the experimental and calculated structures is lower than 1.5 Å. After the validation step, we applied these methods to five case studies for the prediction of the binding of pharmacological active metal species to proteins: (i) the anticancer copper­(II) complex [CuII(Br)­(2-hydroxy-1-naphthaldehyde benzoyl hydrazine)­(indazole)] to human serum albumin (HSA); (ii) one of the active species of antidiabetic and antitumor vanadium compounds, VIVO2+ ion, to carboxypeptidase; (iii) the antiarthritic species [AuI(PEt3)]+ to HSA; (iv) the antitumor oxaliplatin to ubiquitin; (v) the antitumor ruthenium­(II) compound RAPTA-PentaOH to cathepsin B. The calculations suggested that the binding modes are in good agreement with the partial information retrieved from spectroscopic and spectrometric analysis and allowed us, in certain cases, to propose additional hypotheses. This method is an important update in protein–metalloligand docking, which could have a wide field of application, from biology and inorganic biochemistry to medicinal chemistry and pharmacology