Virtual screening, molecular docking and dynamics simulation studies to identify potential agonists of orphan receptor GPR78 targeting CNS disorders

• Published in: Journal of receptors and signal transduction 2024-06, Vol.44 (3), p.82-96
• Main Authors: Garisetti, Vasavi, Varughese, Roslin Elsa, Anandamurthy, Arthikasree, Haribabu, Jebiti, Allard Garrote, Claudio, Dasararaju, Gayathri
• Format: Article
• Language: English
• Subjects: Binding Sites; Central Nervous System Diseases - drug therapy; Central Nervous System Diseases - metabolism; Central Nervous System Diseases - pathology; Drug Discovery; Drug Evaluation, Preclinical; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism
• ISSN: 1079-9893; 1532-4281; 1532-4281
• DOI: 10.1080/10799893.2024.2405488

G protein-coupled receptors (GPCRs) are important targets in drug discovery because of their roles in physiological and pathological processes. Orphan GPCRs are GPCR proteins for which endogenous ligands have not yet been identified and they present interesting avenues for therapeutic intervention. This study focuses on GPR78, an orphan GPCR that is expressed in the central nervous system and linked to neurological disorders. GPR78 has no reported crystal structure and there is limited research. In this study, we have predicted the three dimensional model of GPR78 and its probable binding pocket. Structure-based virtual screening was carried out using the ChemDiv and Enamine REAL databases, followed by induced-fit docking studies to identify potential lead compounds with favorable interactions. These lead compounds were then embedded into a POPC lipid bilayer for a 200 ns molecular dynamics simulation. Free energy landscapes and MM-PBSA analyses were performed to assess the binding energies and conformational dynamics. The results highlight the dynamic nature of GPR78 in the presence of lead compounds and show favorable binding interactions. This study aims to predict a reliable three dimensional model of GPR78 and identify novel lead compounds through a comprehensive approach. The identification of these potential GPR78 agonists represents a significant step in the development of new therapeutics for neurological disorders, highlighting the therapeutic potential of orphan GPR78 in CNS disorders.