A molecular docking study of the interactions between human transferrin and seven metallocene dichlorides

Abstract Human Transferrin (hTf) is a metal-binding protein found in blood plasma and is well known for its role in iron delivery. With only a 30% of its capacity for Fe +3 binding, this protein has the potential ability to transport other metal ions or organometallic compounds from the blood stream to all cell tissues. In this perspective, recent studies have described seven metallocene dichlorides (Cp 2 M(IV)Cl 2 , M(IV) = V, Mo, W, Nb, Ti, Zr, Hf) suitable as anticancer drugs and less secondary effects than cisplatin. However, these studies have not provided enough data to clearly explain how hTf binds and transports these organometallic compounds into the cells. Thus, a computational docking study with native apo-hTf using Sybyl-X 2.0 program was conducted to explore the binding modes of these seven Cp 2 M(IV)Cl 2 after their optimization and minimization using Gaussian 09. Our model showed that the first three Cp 2 M(IV)Cl 2 (M(IV) = V, Mo, W) can interact with apo-hTf on a common binding site with the amino acid residues Leu-46, Ile-49, Arg-50, Leu-66, Asp-69, Ala-70, Leu-72, Ala-73, Pro-74 and Asn-75, while the next four Cp 2 M(IV)Cl 2 (M(IV) = Nb, Ti, Zr, Hf) showed different binding sites, unknown until now. A decreasing order in the total score (equal to −log Kd) was observed from these docking studies: W (5.4356), Mo (5.2692), Nb (5.1672), V (4.5973), Ti (3.6529), Zr (2.0054) and Hf (1.8811). High and significant correlation between the affinity of these seven ligands (metallocenes) for apo-hTf and their bond angles Cp M Cp (r = 0.94, p  2 M(IV)Cl 2 . Experimental data has a good correlation between K A (r = 0.84, p = 0.027) and K d (r = 0.94, p = 0.0014) values and the calculated total scores obtained from our docking experiments. In conclusion, these results suggest that the seven Cp 2 M(IV)Cl 2 used for this study can interact with apo-hTf, and their affinity was directly and inversely proportional to their bond angles Cp M Cp and Cl M Cl, respectively. Our docking studies also suggest that the binding of the first three Cp 2 M(IV)Cl 2 (M(IV) = V, Mo, W) to hTf could abrogate the formation of the hTf-receptor complex, and as a consequence the metallocene-hTf complex might require another transport mechanism in order to get into the cell.