Molecular docking and QSAR studies of aromatase inhibitor androstenedione derivatives

Aromatase (CYP19) inhibitors have emerged as promising candidates for the treatment of estrogen-dependent breast cancer. In this study, a series of androstenedione derivatives with CYP19 inhibitory activity was subjected to a molecular docking study followed by quantitative structure-activity relationship (QSAR) analyses in search of ideal physicochemical characteristics of potential aromatase inhibitors.

The QSAR studies were carried out using both two-dimensional (topological, and structural) and three-dimensional (spatial) descriptors. We also used thermodynamic parameters along with 2D and 3D descriptors. Genetic function approximation (GFA) and genetic partial least squares (G/PLS) were used as chemometric tools for QSAR modelling.

The docking study indicated that the important interacting amino acids in the active site were Met374, Arg115, Ile133, Ala306, Thr310, Asp309, Val370, Leu477 and Ser478. The 17-keto oxygen of the ligands is responsible for the formation of a hydrogen bond with Met374 and the remaining parts of the molecules are stabilized by the hydrophobic interactions with the non-polar amino acids. The C2 and C19 positions in the ligands are important for maintaining the appropriate orientation of the molecules in the active site. The results of docking experiments and QSAR studies supported each other.

The developed QSAR models indicated the importance of some Jurs parameters, structural parameters, topological branching index and E-state indices of different fragments. All the developed QSAR models were statistically significant according to the internal and external validation parameters.