title: The Fragment Molecular Orbital Method Reveals New Insight into the Chemical Nature of GPCR-Ligand Interactions.
abstract: Our interpretation of ligand-protein interactions is often informed by high-resolution structures, which represent the cornerstone of structure-based drug design. However, visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum Mechanics approaches are often too computationally expensive, but one method, Fragment Molecular Orbital (FMO), offers an excellent compromise and has the potential to reveal key interactions that would otherwise be hard to detect. To illustrate this, we have applied the FMO method to 18 Class A GPCR-ligand crystal structures, representing different branches of the GPCR genome. Our work reveals key interactions that are often omitted from structure-based descriptions, including hydrophobic interactions, nonclassical hydrogen bonds, and the involvement of backbone atoms. This approach provides a more comprehensive picture of receptor-ligand interactions than is currently used and should prove useful for evaluation of the chemical nature of ligand binding and to support structure-based drug design.
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Ewa I
authors.initials: EI
authors.lastname: Chudyk
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Gleave
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Matteo
authors.initials: M
authors.lastname: Aldeghi
authors.affiliation: Department of Chemistry, Bridge Institute, University of Southern California , Los Angeles, California 90089, United States.|Laboratory for Structural Biology of GPCRs, Moscow Institute of Physics and Technology , Dolgoprudny 141700, Russia.
authors.forename: Vadim
authors.initials: V
authors.lastname: Cherezov
authors.affiliation: NMRI, National Institute of Advanced Industrial Science and Technology (AIST) , 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan.
authors.forename: Dmitri G
authors.initials: DG
authors.lastname: Fedorov
authors.affiliation: Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin
authors.affiliation: Evotec (U.K.) Ltd. , 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, United Kingdom.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Bodkin
mesh_terms: D000818:Animals; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D043562:Receptors, G-Protein-Coupled