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

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Human Transferrin (hTf) is a blood plasma protein primarily responsible for iron delivery.
• hTf has a limited iron-binding capacity, suggesting potential for transporting other metal ions or organometallic compounds.
• Seven metallocene dichlorides (Cp2M(IV)Cl2) show promise as anticancer agents with fewer side effects than cisplatin.

Purpose of the Study:

• To computationally investigate the binding modes of seven metallocene dichlorides with apo-hTf.
• To elucidate the interaction mechanisms between hTf and these potential anticancer drugs.
• To correlate structural properties of metallocenes with their binding affinity to hTf.

Main Methods:

• Optimization and minimization of seven Cp2M(IV)Cl2 using Gaussian 09.
• Computational docking studies of optimized metallocenes with native apo-hTf using Sybyl-X 2.0.
• Analysis of binding sites, total scores (related to Kd), and correlation with metallocene bond angles.
• Experimental validation using fluorescence spectroscopy to measure hTf-metallocene interactions.

Main Results:

• Cp2M(IV)Cl2 (M(IV)=V, Mo, W) bind to a common site on apo-hTf involving specific amino acid residues.
• Cp2M(IV)Cl2 (M(IV)=Nb, Ti, Zr, Hf) exhibit previously unknown binding sites.
• Binding affinity order correlates with metallocene bond angles (CpMCp and Cl-M-Cl).
• Fluorescence spectroscopy confirms hTf-metallocene interactions, with experimental data correlating well with docking scores.

Conclusions:

• The seven studied Cp2M(IV)Cl2 compounds interact with apo-hTf, with affinity influenced by specific bond angles.
• The binding of V, Mo, and W metallocenes to hTf may hinder receptor complex formation, suggesting alternative cellular uptake pathways.
• These findings provide insights into the transport mechanisms of metallocene-based drugs via hTf.