G protein-coupled estrogen receptor-1 (GPER-1) is a seven transmembrane receptor, responsible for mediating rapid estrogen signaling in many physiological responses in reproductive, nervous, endocrine, immune and cardiovascular systems. Due to unavailability of the crystal structure of GPER-1, a sequential ligand-based virtual screening (LBVS) and structure-based screening (SBVS) approch was used to identify potential GPER-1 modulators. LBVS and SBVS approaches were first validated retrospectively using the Receiver Operating Curve (ROC) plot and the early Enrichment Factor (EF) as statistical matrices. LBVS was performed based on a GPER-1 agonist, G1, as a query model for screening of the eMolecules library using the Rapid Overlay of Chemical Structure (ROCS) and the electrostatic potential screening (EON) approaches. Top-scored hits from LBVS were further screened by SBVS. SBVS was based on generating the homology models of GPER-1 and subsequent molecular docking studies. Using Chemguass4 score, final hit compounds having higher score than the query G1 complound (Chemguass4 score = −11.575) were filterederd out. The top-ranked hits were clustered based on the similarity in their scaffolds. Prospective validation was also performed by synthesising the top hit scaffolds followed by investigating the antiproliferative activity in three different GPER-1 specific cancer cell lines. Preliminary results of this study discovered five new scaffolds which may be serve as ideal lead compounds for further development of novel GPER-1 modulators.

Retrospective and prospective validated high-throughput virtual screening approach for the identification of new 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.