Ligand-mediated structural modulation and membrane stabilization of LPA1 receptor: Insights from molecular dynamics simulations.

Lysophosphatidic acid (LPA) is an important bioactive signaling molecule that activates six distinct G protein-coupled receptors (GPCRs), among which the LPA1 subtype possesses high therapeutic target potential due to its critical roles in malignant tumors, pulmonary fibrosis, inflammation, and neuropathic pain. Recent studies have shown that the small molecule ONO-0740556 can effectively disrupt the overall structure of LPA1 in solution; however, its effects in a native membrane environment remain unclear. According to the Traditional Chinese Medicine Systems Pharmacology Database (TCMS), Dan Shen(Salvia miltiorrhiza) exhibits anti-inflammatory and anti-pulmonary fibrosis properties, and its natural compound cryptoxanthin may serve as a novel LPA1 inhibitor. Here, we employed microsecond-scale all-atom molecular dynamics simulations to systematically compare the structural modulation of LPA1 by ONO-0740556 and cryptoxanthin in a membrane environment. The results indicate that both ligands enlarge the entrance of the LPA1 ligand-binding channel, weaken the interactions between transmembrane helix 7 (TM7) and other structural communities, and reduce hydrophobic interactions between LPA1 and the membrane, thereby inducing membrane structural perturbations. Notably, cryptoxanthin exerts a more pronounced effect in widening the binding channel and selectively attenuating TM7-community interactions. These findings provide atomic-level insights into how small molecules modulate LPA1 structure in its physiologically relevant membrane environment. Such mechanistic understanding not only offers a theoretical basis for the rational design of LPA1-targeted therapeutics but also supports the discovery of natural product-derived inhibitors as viable drug candidates. Moreover, our results highlight potential allosteric sites and dynamic features of LPA1 that could be exploited to develop highly selective modulators, paving the way for more precise therapeutic interventions against LPA1-related diseases.