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.