title: Pathway and mechanism of drug binding to G-protein-coupled receptors.
abstract: How drugs bind to their receptors--from initial association, through drug entry into the binding pocket, to adoption of the final bound conformation, or "pose"--has remained unknown, even for G-protein-coupled receptor modulators, which constitute one-third of all marketed drugs. We captured this pharmaceutically critical process in atomic detail using the first unbiased molecular dynamics simulations in which drug molecules spontaneously associate with G-protein-coupled receptors to achieve final poses matching those determined crystallographically. We found that several beta blockers and a beta agonist all traverse the same well-defined, dominant pathway as they bind to the β(1)- and β(2)-adrenergic receptors, initially making contact with a vestibule on each receptor's extracellular surface. Surprisingly, association with this vestibule, at a distance of 15 Å from the binding pocket, often presents the largest energetic barrier to binding, despite the fact that subsequent entry into the binding pocket requires the receptor to deform and the drug to squeeze through a narrow passage. The early barrier appears to reflect the substantial dehydration that takes place as the drug associates with the vestibule. Our atomic-level description of the binding process suggests opportunities for allosteric modulation and provides a structural foundation for future optimization of drug-receptor binding and unbinding rates.
authors.affiliation: DE Shaw Research, New York, NY 10036, USA. Ron.Dror@DEShawResearch.com
authors.forename: Ron O
authors.initials: RO
authors.lastname: Dror
authors.forename: Albert C
authors.initials: AC
authors.lastname: Pan
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Arlow
authors.forename: David W
authors.initials: DW
authors.lastname: Borhani
authors.forename: Paul
authors.initials: P
authors.lastname: Maragakis
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.forename: Huafeng
authors.initials: H
authors.lastname: Xu
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
mesh_terms: D000526:Alprenolol / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003890:Desiccation; D005110:Extracellular Space / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D004364:Pharmaceutical Preparations; D011485:Protein Binding; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000526:Alprenolol