Lubna Ahmed, Reham Hossam, Mariem Adel, Nourhan Hassan, Muhammed Ismail, Maria Attallah and Mahmoud Salama Ahmed
Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City Cairo-Suez Desert Road Cairo, Egypt
Breast Cancer is the second leading cause for death among women worldwide. Estrogen receptor is known molecular target affiliated with the treatment of breast cancer. Comprehensive virtual screening study was conducted exploring different pharmacophores using ZINC Pharmer database. The pharmacophore generation revealed the necessity of presence of two hydrophobic regions, hydrogen bond donor, and hydrogen bond acceptor. This leads to generation of novel scaffold ZINC 89808250 (5-[(2-bromo-5-hydroxy-phenyl) methyl amino]-1H-indazole-3-carboxamide) via scaffold hopping after opening of the estradiol ring. This was followed by, design of virtual library comprising 50 virtual ligands, the design phase involved different strategies such as, bio-Isosterism, ring variation, and ring opening. The deigned ligands were energy minimized using MMFF94, and docked along with estrogen receptor co-crystallized with estradiol (PDB ID: 1A52) using Open Eye molecular Modeling software, and further validated using Auto-Dock Vina Tools. Ten ligands showed better binding affinity ranged from -12.85 Kcal/ mol to -10.8 Kcal/mol, compared to the binding affinity of the estradiol of -10.5 Kcal/mol. The most promising ligand (RLM-9) showed better hydrophobic – hydrophobic interaction and two hydrogen bonds between –OH group and Arg:394A and –NH group and Leu:346A. These findings suggest the potential of novel synthetically feasible analogs targeting estrogen receptor.