Structural analysis and ensemble docking revealed the binding modes of selected progesterone receptor modulators

Area of Science:

• Pharmacology
• Molecular Biology
• Drug Discovery

Background:

• Uterine fibroids (UF) significantly impact women's health, causing heavy bleeding and fertility issues.
• Current treatments like selective progesterone receptor modulators (SPRMs) have been withdrawn due to side effects.
• There is a critical need for novel, effective UF therapeutics with improved safety profiles.

Purpose of the Study:

• To investigate the structural basis of progesterone receptor (PR) interactions with SPRMs.
• To identify key molecular features for designing new UF therapeutics.
• To provide a resource for drug discovery scientists targeting UF.

Main Methods:

• Comparative analysis of reported human PR crystal structures.
• Ensemble docking approach to elucidate binding modes of four SPRMs.
• Molecular dynamics (MD) simulations to assess ligand selectivity and stability.

Main Results:

• Identified five conserved water molecules crucial for ligand binding and PR stability.
• Demonstrated that studied SPRMs exhibit preferential selectivity for specific PR conformations.
• Provided insights into the structure-activity relationships of SPRMs and human PR.

Conclusions:

• The study offers a detailed understanding of PR-ligand interactions relevant to UF.
• Findings can guide the development of novel SPRMs with enhanced efficacy and safety.
• This research serves as a valuable foundation for future UF drug discovery efforts.