Quantitative structure activity relationship (QSAR) study of estrogen derivatives based on descriptors of energy and softness.

Quantum chemical interaction of estrogen derivatives with their receptor has been explored by using Klopman atomic softness. Four series of estrogen derivatives were taken from the literature and the structure of receptor (PDB code 1QKT) was obtained from the protein databank. It is proposed that three Lys, a His, a Tyr and a Cys residues are important for binding. The basic softness values (E(m)(double dagger)) and acidic softness values (E(n)(double dagger)) of all atoms of estrogen derivatives were evaluated. The required parameters for Klopman equation were taken from PM3 results. The highest E(n)(double dagger) values for each molecules and highest E(m)(double dagger) value for each residue were identified and Delta E(nm)(double dagger) has been derived using them. The lowest Delta E(nm)(double dagger) values were used in addition to Q(min) (highest negative charge), Delta H(f)(0) (heat of formation), E(T) (total energy), and E(E) (electronic energy). Multiple linear regression analysis was employed to correlate the variation of relative binding affinity values. The analyses show that Delta E(nm)(double dagger) values in combination with other descriptors provide significant correlation with relative binding affinity values. The result underscores that carbonyl oxygen of the receptor is important for interaction with estrogen derivatives. This model could be utilized to predict the binding affinity of a new compound of this series.