title: Using the fragment molecular orbital method to investigate agonist-orexin-2 receptor interactions.
abstract: The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity and is essential for an efficient structure-based drug discovery (SBDD) process. Clearly, to begin SBDD, a structure is needed, and although there has been fantastic progress in solving G-protein-coupled receptor (GPCR) crystal structures, the process remains quite slow and is not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of X-ray crystallography to impact the drug discovery process for GPCR targets in 'real-time' and hence there is still a need for other practical and cost-efficient alternatives. We present here an approach that integrates our previously described hierarchical GPCR modelling protocol (HGMP) and the fragment molecular orbital (FMO) quantum mechanics (QM) method to explore the interactions and selectivity of the human orexin-2 receptor (OX2R) and its recently discovered nonpeptidic agonists. HGMP generates a 3D model of GPCR structures and its complexes with small molecules by applying a set of computational methods. FMO allowsab initioapproaches to be applied to systems that conventional QM methods would find challenging. The key advantage of FMO is that it can reveal information on the individual contribution and chemical nature of each residue and water molecule to the ligand binding that normally would be difficult to detect without QM. We illustrate how the combination of both techniques provides a practical and efficient approach that can be used to analyse the existing structure-function relationships (SAR) and to drive forward SBDD in a real-world example for which there is no crystal structure of the complex available.
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K. Alexander.Heifetz@Evotec.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Matteo
authors.initials: M
authors.lastname: Aldeghi
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
authors.forename: Ewa I
authors.initials: EI
authors.lastname: Chudyk
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: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, U.K.
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Bodkin
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, U.K.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Biggin
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D000068797:Orexins / Q000378:metabolism*; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000068797:Orexins; D043562:Receptors, G-Protein-Coupled
keywords: G-protein-coupled receptor (GPCR); chemical interactions; computational; drugs; fragment molecular orbital (FMO); modelling; receptor; structure-based drug-discovery (SBDD)