PIF2025 - ENFOQUE SOBRE EL RECEPTOR HUERFANO GPR18: ESTRATEGIAS COMPUTACIONALES, SINTETICAS Y TERAPÉUTICAS - (PID2024-158255OB-I00)

Over the past years, we have been working on diverse research lines related to the endocannabinoid system including the therapeutic target CB1, CB2, and GPR55 receptors. With this proposal, we want to focus our research on the understanding of GPR18 receptor and its modulation. Our preliminary data allowed us to discover selective GPR18 ligands. With this proposal, we are expecting improving their potency and finding new scaffolds to go through a drug discovery program leading to innovation in inflammation and cancer treatment. The proposal is based on molecular modeling, ligand synthesis, signaling studies, and pharmacological assays for therapeutic applications. Progress in structural biology tools such as X-ray crystallography, cryo-EM, and NMR spectroscopy has enhanced our understanding of G-protein coupled receptors (GPCRs) structures. Although the GPR18 structure remains unresolved, these advances will allow to build novel GPR18 models and design new ligands. Then, the new ligands will be synthesized using traditional synthetic strategies for this project while awaiting future access to machine learning platforms for synthesis optimization. Understanding GPR18 signaling pathways is critical. To address this complexity, the project will use different pharmacological strategies. By selecting the most promising ligand candidates, the project aims to evaluate their anticancer properties, anti-inflammatory properties being undertaken by collaborators.