The interaction of metallodrugs with
proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various VIVO compounds with
lysozyme, a prototypical model of
protein receptor. Five VIVO-
flavonoid drug candidates formed by
quercetin (que),
morin (mor),
7,8-dihydroxyflavone (7,8-dhf),
chrysin (chr), and
5-hydroxyflavone (5-hf)-effective against several
osteosarcoma cell lines-and two benchmark VIVO species of
acetylacetone (acac) and
catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL2] and the surface residues of
lysozyme. The qualitative strength of the interaction from EPR is [VO(que)2]2- ≈ [VO(mor)2] > [VO(7,8-dhf)2]2- > [VO(chr)2] ≈ [VO(5-hf)2] > [
VO(acac)2] ≈ [VO(cat)2]2-. This observation is compared with
protein-
ligand docking calculations with
GOLD software examining the GoldScore scoring function ( F), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the Fmax value and depends on the number of
OH or CO groups of the
ligands that can interact with different sites on the
protein surface and, more particularly, with those in the vicinity of the active site of the
enzyme. The interaction strength determines the type of signal revealed ( rigid limit, slow tumbling, or isotropic) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous
solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic
metal species with a generic
protein.