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Analyzing GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method

Heifetz, A; James, T; Southey, M; Morao, I; Fedorov, DG; Bodkin, MJ; Townsend-Nicholson, A; (2020) Analyzing GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method. Methods in Molecular Biology , 2114 pp. 163-175. 10.1007/978-1-0716-0282-9_11. Green open access

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Abstract

G-protein-coupled receptors (GPCRs) have enormous physiological and biomedical importance, and therefore it is not surprising that they are the targets of many prescribed drugs. Further progress in GPCR drug discovery is highly dependent on the availability of protein structural information. However, the ability of X-ray crystallography to guide the drug discovery process for GPCR targets is limited by the availability of accurate tools to explore receptor-ligand interactions. Visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum mechanics (QM) approaches are often too computationally expensive to be of practical use in time-sensitive situations, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed, and the ability to reveal key interactions that would otherwise be hard to detect. Integration of GPCR crystallography or homology modelling with FMO reveals atomistic details of the individual contributions of each residue and water molecule toward ligand binding, including an analysis of their chemical nature. Such information is essential for an efficient structure-based drug design (SBDD) process. In this chapter, we describe how to use FMO in the characterization of GPCR-ligand interactions.

Type: Article
Title: Analyzing GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/978-1-0716-0282-9_11
Publisher version: https://doi.org/10.1007/978-1-0716-0282-9_11
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Chemical interactions, Computational, Computer-aided drug design (CADD), Drugs, Fragment molecular orbital method (FMO), G-protein-coupled receptors (GPCR), General atomic and molecular electronic structure system (GAMESS), Modelling, Pair interaction energy (PIE), Pair interaction energy decomposition analysis (PIEDA), Quantum mechanics (QM), Receptor, Structure-based drug design (SBDD)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10093312
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