In silico ligand docking approaches to characterise the binding of known allosteric modulators to the glucagon-like peptide 1 receptor and prediction of ADME/Tox properties

Odoemelam, C.S. ORCID: 0000-0002-9622-2075, Hunter, E., Simms, J., Ahmad, Z., Chang, M.-W., Percival, B. ORCID: 0000-0002-8769-8979, Williams, I.H., Molinari, M., Kamerlin, S.C.L. and Wilson, P.B. ORCID: 0000-0003-0207-2246, 2022. In silico ligand docking approaches to characterise the binding of known allosteric modulators to the glucagon-like peptide 1 receptor and prediction of ADME/Tox properties. Applied Biosciences, 1 (2), pp. 143-162. ISSN 2813-0464

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Abstract

The glucagon-like peptide 1 receptor (GLP-1R) is a member of the family (or class) B G-protein-coupled receptor (GPCR). The receptor is a regulator of insulin and a key target in treating Type 2 diabetes mellitus. In this investigation, computational chemistry techniques such as molecular docking were combined with in silico ADME/Tox predictions to determine the position and structure of the allosteric binding site, as well as to examine how the allosteric modulators bind to the binding site. In silico evaluation was used to evaluate the ADME/Tox properties of the allosteric modulators. The findings of the ligand docking studies suggest that the allosteric binding site is situated around the transmembrane (TM) domain TM 6 of the receptor in the active state. ADME/Tox characterisation of the allosteric modulators demonstrate that compounds 1–3 (2,6,7-trichloro-3-(trifluoromethyl)quinoxaline, 1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-6,6-dimethyl-3-(methylsulfonyl)-6,7-dihydrobenzo[c]thiophen-4(5H)-one, 2-((4-chlorophenyl)thio)-3-(trifluoromethyl)quinoxaline, respectively) complied with the traditional method of evaluating drug-likeness; Lipinski’s rule of 5. The allosteric modulator compound 4 (3-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)phenyl cyclohexanecarboxylate) failed to comply with Lipinski’s rule of five as a result of having a logP value of over 5.6. Moreover, molecular docking studies provide insights into potential allosteric binding sites and possible interactions. Finally, the in silico ADME/Tox study results are described as relevant to developing a viable drug candidate.

Item Type: Journal article
Publication Title: Applied Biosciences
Creators: Odoemelam, C.S., Hunter, E., Simms, J., Ahmad, Z., Chang, M.-W., Percival, B., Williams, I.H., Molinari, M., Kamerlin, S.C.L. and Wilson, P.B.
Publisher: MDPI AG
Date: 2022
Volume: 1
Number: 2
ISSN: 2813-0464
Identifiers:
NumberType
10.3390/applbiosci1020010DOI
1579406Other
Rights: Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Divisions: Schools > School of Animal, Rural and Environmental Sciences
Schools > School of Science and Technology
Record created by: Linda Sullivan
Date Added: 04 Aug 2022 15:46
Last Modified: 04 Aug 2022 15:46
URI: http://irep.ntu.ac.uk/id/eprint/46831

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