A Combined Molecular Docking and Electronic Structure Study for a Breast Cancer Drug Design

Additional information available the chapter Abstract The molecular docking of tamoxifen ’ s metabolites, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-N-desmethyl-tamoxifen, in estrogen and progesterone hor- mone receptors was studied in aqueous solution. The metabolites 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-N-desmethyl-tamoxifen exhibit a binding energy in the estrogen receptor cavity of (cid:1) 10.69 kcal/mol, (cid:1) 10.9 kcal/mol, and (cid:1) 11.35 kcal/mol, respectively, and (cid:1) 1.45 kcal/mol, (cid:1) 9.29 kcal/mol, and (cid:1) 0.38 kcal/mol in the progesterone receptor. This indicates a spontaneous interaction between the metabolites and the active sites in the hormone receptors. Docking has an adequate accuracy for both receptors, and from this calculation the active site residues were defined for the different metabolites and the estrogen and progesterone receptors. Also, the chemical reactivity of the amino acids of the active sites of each metabolite was determined. These reactivity properties were obtained within the framework of density functional theory, using the functional M06 with the basis set 6-31G (d). The results indicate that in the estrogen receptor, the highest charge transfer of the three analyzed metabolites is in the union of the metabolite and the Leu346-Thr347 residue. The progesterone receptor shows minor tendency to react with higher hardness values than the estrogen receptor. The hydrogen bonds are three for the estrogen receptor in two different metabolites, while in progesterone only one is formed with the N-desmethyl-tamoxifen metabolite.