A 3D QSAR Model of 17β‐HSD1 Inhibitors Based on a Thieno[2,3‐d]pyrimidin‐4(3H)‐one Core Applying Molecular Dynamics Simulations and Ligand–Protein Docking

The 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) enzyme plays a crucial role in female hormonal regulation by catalysing the NADPH-dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17β-HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report the plausible binding modes and a 3D QSAR model of 17β-HSD1 inhibitors based on a (di)cycloolkenothieno[2,3-d]pyrimidin-4(3H)-one core. Two generated enzyme complexes with potent inhibitors were subjected to molecular dynamics simulation to mimic the dynamic process of inhibitor binding. A set of 17β-HSD1 inhibitors based on the thieno[2,3-d]pyrimidin-4(3H)-one core were docked into the resulting active site, and a CoMFA model employing the most extensive training set to date was generated. The model was validated with an external test set. Active site residues involved in inhibitor binding and CoMFA fields for steric and electrostatic interactions were identified. The model will be used to guide structural modifications of 17β-HSD1 inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core in order to improve the biological activity as well as in the design of novel 17β-HSD1 inhibitors.