Molecular Docking Analysis of Steroid-based Copper Transporter 1 Inhibitors.

Copper transporter 1 (CTR1) represents an important determinant of cisplatin resistance. A series of 35 semi-substituted steroids were recently investigated on cisplatin-resistant CTR1-expressing A2780cis ovarian carcinoma cells as well as their parental sensitive counterparts regarding their cytotoxic and resistance-reversing features. In the present investigation, three compounds (4, 5, 25) were selected for molecular docking analysis on the homology-modelled human CTR1 transmembrane domain. Steroids 4, 5 and 25 interacted with CTR1 at a similar docking pose and with even higher binding affinities than the known CTR1 inhibitor, cimetidine. Applying the defined docking mode, the binding energies were found to be -7.15+/-<0.001 kcal/mol (compound 4), -8.71+/-0.06 kcal/mol (compound 5), -7.63+/-0.01 kcal/mol (compound 25), and -5.05+/-0.02 kcal/mol (for cimetidine). These steroids have the potential for further development as CTR1 inhibitors overcoming cisplatin resistance.