Estrogen receptors are important regulators of the growth of breast tumors. The complexity of estrogen signaling became apparent when some of its effects did not fit the time course for transcriptional signalling. Estrogen receptors (ER), ERα and ERβ are classical steroid receptors that typically dimerize and translocate to the nucleus after ligand binding while 7-transmembrane G protein-coupled estrogen receptor 1 (GPER-1/GPR30) initiates non-genomic effects of estrogens in the cytosol. GPER-1 activation mediates many of the rapid cellular signaling events associated with estrogen activity, as opposed to the nuclear ERs. GPER-1 modulators represent a new therapeutic approach for many disease or condition involving estrogen. In the absence of crystal structure of GPER-1, ligand-based approaches are useful approaches in which Pharmacophore modeling is a widely used strategy for finding new hit molecules. Herein, this study was designed based upon in silico pharmacophore screening. A Common feature pharmacophore model based on three selective ligands for GPER-1 was developed. The developed common feature pharmacophore model was comprised of seven features: two hydrogen bond acceptor, two hydrogen bond donor and three hydrophobic units. The pharmacophore model was retrospectively validated using known GPER-1 active ligand and Decoys datasets. Validated model was subsequently used in the virtual screening of ASINEX Gold and Platinum databases to identify new GPER-1 scaffolds. The hit compounds were filtered based on pharmacophore fit score higher than 4.0. Additionally, the molecular docking study was also applied to evaluate the affinity of the hit compounds towards the GPER-1. Twelve compounds were identified as final hits, in which five compounds showed a new scaffold and higher affinity towards GPER-1 than the selective modulators. Further dynamic stability of top five hits was also evaluated by molecular dynamic simulation. Present work revealed five new scaffolds as GPER-1 ligands which are underway for their in vitro biological evaluation in GPER-1 specific cancer cell lines.

Pharmacophore-based virtual screening: Identification of new scaffolds as GPER-1 modulators

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.