Probing the origins of 17β-hydroxysteroid dehydrogenase type 1 inhibitory activity via QSAR and molecular docking.

It is generally known that proliferation of human breast cancer cells is stimulated by excess estrogen namely 17β-estradiol. Therefore, reduction of 17β-estradiol production by inhibiting 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an interesting route for breast cancer treatment particularly during adjuvant therapy. This study investigated the structure-activity relationship of 17β-HSD1 inhibitors as to gain insights and understanding on the origins of 17β-HSD1 inhibitory activities. To meet this goal, multiple linear regression model was constructed and correspondingly the results revealed good predictivity (N = 31, R(2) = 0.9438, Q(2) = 0.8530). The model suggested that low molecular weight and energy were preferred as 17β-HSD1 inhibitors. Additionally, high molecular flexibility and high number of hydrogen bond donors were also shown to be important that is in correspondence to previously reported pharmacophore model of 17β-HSD1 inhibitors. Furthermore, molecular docking of inhibitors to 17β-HSD1 followed by anchor analysis suggested that three different pockets comprising of hydrogen bonding sites 1 and 2 as well as van der Waals contacts contributed to protein-ligand interactions. Post-docking analysis of potent compound 9 with 17β-HSD1 suggested that the binding modality was similar to the binding of substrate (i.e. estradiol) and its analog (i.e. equilin). Such information is useful in guiding the further design of novel and robust 17β-HSD1 inhibitors.