Reaction of dirhodium and diruthenium paddlewheel tetraacetate complexes with nucleophilic protein sites: A computational study

The biomolecular affinity of three paddlewheel dinuclear complexes Rh-2(mu-O2CCH3)(4)(H2O)(2), Ru-2(mu-O2CCH3)(4)(H2O)Cl, [Ru-2(mu-O2CCH3)(4)(H2O)(2)](+) for the binding at cancer-specific protein targets was determined by means of DFT approaches. Thermodynamics of axial ligand substitution reaction by models of suitable protein sites was investigated in order to assess the binding selectivity displayed by the paddlewheel complexes. Both Rh-2(mu-O2CCH3)(4)(H2O)(2) and Ru-2(mu-O2CCH3)(4)(H2O)Cl resulted to react favorably with most of the examined models of the protein side chains, with higher exergodicity demonstrated in the reaction of Arg, Cys, His, Lys, Sec, thus showing a limited selectivity. On the other hand, we identified Sec and His as the most suitable targets of the examined paddlewheel complexes, while Arg and Lys are expected to be also targetable at higher pH. Therefore, our calculations showed how both dirhodium and, majorly, diruthenium examined complexes undergo to a certain degree of destabilization upon the binding at nucleophilic protein sites. The presented computational results allowed us to shed light onto the protein sites' affinity and on the therapeutic potential of both Rh-2(mu-O2CCH3)(4)(H2O)(2) and Ru-2(mu-O2CCH3)(4)(H2O)Cl, and provided for a structural basis for the development of newly designed paddlewheel complexes.