Entry from the Lipid Bilayer: A Possible Pathway for Inhibition of a Peptide G Protein-Coupled Receptor by a Lipophilic Small Molecule

The pathways that G protein-coupled receptor (GPCR) ligands follow as they bind to or dissociate from their receptors are largely unknown. Protease-activated receptor-1 (PAR1) is a GPCR activated by intramolecular binding of a tethered agonist peptide that is exposed by thrombin cleavage. By contrast, the PAR1 antagonist vorapaxar is a lipophilic drug that binds in a pocket almost entirely occluded from the extracellular solvent. The binding and dissociation pathway of vorapaxar is unknown. Starting with the crystal structure of vorapaxar bound to PAR1, we performed temperature-accelerated molecular dynamics simulations of ligand dissociation. In the majority of simulations, vorapaxar exited the receptor laterally into the lipid bilayer through openings in the transmembrane helix (TM) bundle. Prior to full dissociation, vorapaxar paused in metastable intermediates stabilized by interactions with the receptor and lipid headgroups. Derivatives of vorapaxar with alkyl chains predicted to extend between TM6 and TM7 into the lipid bilayer inhibited PAR1 with apparent on rates similar to that of the parent compound in cell signaling assays. These data are consistent with vorapaxar binding to PAR1 via a pathway that passes between TM6 and TM7 from the lipid bilayer, in agreement with the most consistent pathway observed by molecular dynamics. While there is some evidence of entry of the ligand into rhodopsin and lipid-activated GPCRs from the cell membrane, our study provides the first such evidence for a peptide-activated GPCR and suggests that metastable intermediates along drug binding and dissociation pathways can be stabilized by specific interactions between lipids and the ligand.

Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.

Peer-reviewed research on leech salivary compounds and their pharmacology. Indexed in PubMed and verified against the NCBI record.

Explore cómo esta investigación se conecta con la práctica clínica

More peer-reviewed studies in Farmacología salival.

• Novel Leech Antimicrobial Peptides — Hirunipins — Kumar et al. (2025)
• 434 Salivary Proteins — Integrated Proteomics of Hirudo medicinalis — Liu et al. (2019)
• Medicinal Leech Genome Assembly — Anticoagulant Gene Catalog — Kvist et al. (2020)
• Effects of hirudotherapy on liver functions, lipid profile, and insulin sensitivity in rats with metabolic syndrome — Bilden A et al. (2026)
• [Research progress in hirudin fusion protein--review] — Zhang C et al. (2007)
• A unique proteolytic fragment of human fibrinogen containing the A alpha COOH-terminal domain of the native molecule — Kirschbaum NE, Budzynski AZ (1990)
• Updates on Use and Monitoring of Direct Thrombin Inhibitors — Navaei A et al. (2026)
• Production and functional characteristics of a novel hirudin variant with better anticoagulant activities than bivalirudin — Ge P et al. (2025)
• Traditional Chinese medicine in the treatment of diabetic kidney disease: the mechanisms of signaling pathways regulations — Li W et al. (2026)
• Prostaglandin E1 is an efficient molecular tool for forest leech blood sucking — Zheng F et al. (2021)

Browse all ASH-analysed research →