Structural and Energetic Characterization of the Binding Mechanism of a new antagonist moleucle of GP-BAR1 through Metadynamics Simulations

Research area
Computational Medicine and Life Sciences
Internal groups
Medicinal Chemistry and Drug Design

The degradation of cholesterol produces bile acids (BAs) that are physiological ligands of different receptors. The BAs are responsible for the activation of numerous cellular mechanisms through the interaction with membrane receptors belonging to the G-Protein Coupled Receptors (GPCRs) family. The most studied BAs receptors are the cell membrane GP-BAR1 and the nuclear farnesoid X receptor (FXR). In particular, GP-BAR1 is involved in lipids and glucose metabolism defects such as nonalcoholic steatohepatitis, hypercholesterolaemia, hypertriglyceridaemia, and type 2 diabetes mellitus. In this scenario the possibility to develop a selective antagonist of this receptor is acquiring year after year a large relevance in the pharmacological field. In this work we have characterize at atomic level the binding mode of a very promising molecule with antagonistic activity demonstrated through experimental assays. The use of metadynamics simulations allowed us to deeply describe the free energy landscape of the receptor-ligand binding process that is a milestone for drug discovery. The ability to modulate the activity of GP-BAR1 through antagonist compounds is a solid pharmacological strategy for treatment of numerous diseases.


Prof. Dr. Vittorio Limongelli; ; PI; ICS


Researcher Daniele Di Marino; ; ICS


University of Perugia;

University of Naples;



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