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.
Original language | English |
---|---|
Pages (from-to) | 143-162 |
Number of pages | 20 |
Journal | Applied Biosciences |
Volume | 1 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2 Aug 2022 |
Bibliographical note
© 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/
Keywords
- ADME/Tox
- GLP-1R
- ligand binding
- allosteric binding site
- allosteric modulator
- GPCR