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Rapid and Accurate Assessment of GPCR-Ligand Interactions Using the Fragment Molecular Orbital-Based Density-Functional Tight-Binding Method

Morao, I; Fedorov, DG; Robinson, R; Southey, M; Townsend-Nicholson, A; Bodkin, MJ; Heifetz, A; (2017) Rapid and Accurate Assessment of GPCR-Ligand Interactions Using the Fragment Molecular Orbital-Based Density-Functional Tight-Binding Method. Journal of Computational Chemistry , 38 (23) pp. 1987-1990. 10.1002/jcc.24850. Green open access

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Abstract

The reliable and precise evaluation of receptor–ligand interactions and pair-interaction energy is an essential element of rational drug design. While quantum mechanical (QM) methods have been a promising means by which to achieve this, traditional QM is not applicable for large biological systems due to its high computational cost. Here, the fragment molecular orbital (FMO) method has been used to accelerate QM calculations, and by combining FMO with the density-functional tight-binding (DFTB) method we are able to decrease computational cost 1000 times, achieving results in seconds, instead of hours. We have applied FMO-DFTB to three different GPCR–ligand systems. Our results correlate well with site directed mutagenesis data and findings presented in the published literature, demonstrating that FMO-DFTB is a rapid and accurate means of GPCR–ligand interactions.

Type: Article
Title: Rapid and Accurate Assessment of GPCR-Ligand Interactions Using the Fragment Molecular Orbital-Based Density-Functional Tight-Binding Method
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/jcc.24850
Publisher version: http://dx.doi.org/10.1002/jcc.24850
Language: English
Additional information: © 2017 Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, drug discovery, protein, ab initio, DFTB, MP2, GPCR, P2Y(12) RECEPTOR, COMPLEX, CHEMISTRY, DRUG
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/1564678
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