Discovery of Chemical Scaffolds as Lysophosphatidic Acid Receptor 1 Antagonists: Virtual Screening, In Vitro Validation, and Molecular Dynamics Analysis.

Lysophosphatidic acid receptor 1 (LPAR1) is an emerging therapeutic target for numerous human diseases including fibrosis. However, the limited number of available core structures of LPAR1 antagonists has prompted the need for novel chemical templates. In this study, we conducted a high-throughput virtual screening to discover potential new scaffolds. We tested three existing crystal structures alongside an AlphaFold model to evaluate their suitability in structure-based virtual screening, finding that the crystal structures show superior performance compared with the predictive model. Furthermore, we also found that enhancing the precision in the screening process did not necessarily improve the enrichment of hits. From the screening campaign, we identified five structures that were validated using an LPAR1-dependent calcium flux assay. To gain a deeper insight into the protein-ligand interaction, we extensively analyzed the binding modes of these compounds using in silico techniques, laying the groundwork for the discovery of novel LPAR1 antagonists.