Molecular Simulation, Pharmacophore Mapping, and 3D QSAR Modeling on Chromene-Based SERDs

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Estrogen receptor alpha (ERα) is a key target for ER-positive breast cancer treatment.
• Current selective estrogen receptor degraders (SERDs) face bioavailability limitations, and resistance can emerge due to ERα mutations.
• Developing novel SERDs with improved efficacy and overcoming resistance mechanisms is crucial.

Purpose of the Study:

• To elucidate the structure-activity relationship of chromene-based compounds as potential SERDs.
• To design and predict the activity of novel ERα-targeting agents.
• To identify compounds with enhanced binding affinity and therapeutic potential.

Main Methods:

• Pharmacophore mapping and Gaussian field-based 3D Quantitative Structure-Activity Relationship (QSAR) modeling.
• Molecular docking of the most active analogue into the ERα ligand binding domain (PDB ID: 6V8T).
• Molecular dynamics simulations and MM/GBSA binding-free energy calculations.

Main Results:

• A five-point pharmacophore hypothesis (HHHRR_1) was generated, guiding the development of a robust 3D QSAR model (q2=0.8, r2=0.94).
• Compound 18 exhibited stable binding to ERα, with a calculated binding free energy (ΔGbind MM/GBSA) of -67.03 kcal/mol.
• Compound 18 demonstrated superior binding affinity compared to fulvestrant (ΔGbind MM/GBSA = -64.76 kcal/mol), indicating enhanced target engagement.

Conclusions:

• Integrated computational modeling successfully identified key molecular features for potent ERα degradation.
• Compound 18, with its enhanced binding affinity, represents a promising lead for developing novel oral SERDs.
• Optimizing the chromene scaffold can lead to new therapeutic agents for ER-positive breast cancer with improved potential.