Ligand-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations of New β-Estrogen Receptor...

Area of Science:

• Pharmacology and Drug Discovery
• Computational Chemistry
• Endocrinology

Background:

• Obesity is a global health crisis requiring novel therapeutic strategies.
• Estrogen receptor beta (ERβ) activation promotes weight loss, presenting a viable drug target for obesity management.
• Existing treatments for obesity have limitations, necessitating the exploration of new molecular targets and drug candidates.

Purpose of the Study:

• To identify and predict novel small molecules that can activate estrogen receptor beta (ERβ).
• To explore drug repositioning strategies by screening FDA-approved drugs for ERβ activity.
• To evaluate the stability, safety, and potential efficacy of candidate molecules through computational methods.

Main Methods:

• Ligand-based virtual screening of chemical databases (ZINC15, PubChem, Molport) using known ERβ ligand structures.
• Molecular docking simulations of FDA-approved drugs to identify potential ERβ repositioning candidates.
• Molecular dynamic simulations and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions for selected compounds.

Main Results:

• Compounds 1, 2, and 6 demonstrated significant binding stability within the ERβ active site (RMSD < 3.3 Å).
• Molecular dynamics simulations confirmed that these compounds do not adversely affect ERβ structural integrity or compactness.
• In silico ADMET profiling indicated that the identified compounds possess favorable safety profiles, suggesting low toxicity.

Conclusions:

• The study successfully identified novel small molecules with the potential to activate ERβ.
• These ERβ ligands exhibit promising stability and safety profiles, making them suitable candidates for further drug development.
• The findings suggest that targeting ERβ with these novel compounds could offer a new therapeutic avenue for controlling obesity.