Projects / Drug Design / Structure Based Design
CADD applied on inhibitor development

Hybrid Discovery: Targeted Glucocorticoid Receptor (GR) Modulation

This study utilized a dual-strategy approach to explore the Glucocorticoid Receptor, targeting both classical genomic and non-genomic pathways. By combining large-scale database mining (ZINC) with structure-based combinatorial chemistry, we identified novel scaffolds with high potential for selective modulation.

The Dual-Strategy Approach

Glucocorticoid Receptor Complex

Visualization of both Strategies

Strategy I: Genomic Pathway Optimization

  • Conducted high-throughput virtual screening of the ZINC database for glucocorticoid analogs.
  • Utilized rational substituent design to enhance potency and elucidate pathway-specific effects.

Strategy II: Non-Genomic Pathway Exploration

  • Initiated discovery via ligand-based similarity searches (homologs) to identify non-traditional candidates.
  • Validated "best-fit" candidates through bench-top assays and iterative binding evaluations.

Advanced Optimization & Refinement

  • Combinatorial Chemistry: Employed a combinatorial approach to rapidly explore the chemical space surrounding lead scaffolds.
  • Iterative SAR Development: Integrated experimental assay data to re-mold and refine substituents for improved receptor fit.
  • ADMET Integration: Rigorous computational assessment of absorption, metabolism, and potential toxicity profiles for all novel entities.