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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Oncology

Background:

• Human breast cancer cell proliferation is stimulated by excess estrogen, specifically 17β-estradiol.
• Inhibiting 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) offers a therapeutic strategy for breast cancer, particularly in adjuvant therapy.
• Understanding the structure-activity relationships of 17β-HSD1 inhibitors is crucial for designing effective drugs.

Purpose of the Study:

• To investigate the structure-activity relationship of 17β-HSD1 inhibitors.
• To gain insights into the origins of 17β-HSD1 inhibitory activities.
• To guide the design of novel and robust 17β-HSD1 inhibitors.

Main Methods:

• Construction of a multiple linear regression model (N = 31) to predict inhibitory activity.
• Analysis of molecular descriptors including molecular weight, energy, flexibility, and hydrogen bond donors.
• Molecular docking and anchor analysis of inhibitors with 17β-HSD1.

Main Results:

• The multiple linear regression model demonstrated good predictivity (R(2) = 0.9438, Q(2) = 0.8530).
• Preferred inhibitor characteristics include low molecular weight and energy, high molecular flexibility, and numerous hydrogen bond donors.
• Molecular docking revealed interactions within three distinct pockets of 17β-HSD1, involving hydrogen bonding and van der Waals forces.
• The binding mode of a potent inhibitor (compound 9) resembles that of the natural substrate (estradiol).

Conclusions:

• The study successfully elucidated key structural features essential for potent 17β-HSD1 inhibition.
• Findings provide valuable guidance for the rational design of new breast cancer therapeutic agents targeting 17β-HSD1.
• The identified structure-activity relationships and binding interactions can accelerate the development of novel inhibitors.