Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening
Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon...
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MDPI AG
2021-06-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/7/929 |
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doaj-e0f406affb7b466fa714fe033544fada2021-07-23T13:31:55ZengMDPI AGBiomolecules2218-273X2021-06-011192992910.3390/biom11070929Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual ScreeningQingtong Zhou0Wanjing Guo1Antao Dai2Xiaoqing Cai3Márton Vass4Chris de Graaf5Wenqing Shui6Suwen Zhao7Dehua Yang8Ming-Wei Wang9School of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaThe National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaThe National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaThe National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaAmsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, 1081 Amsterdam, The NetherlandsAmsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, 1081 Amsterdam, The NetherlandsiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaThe National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, ChinaSchool of Basic Medical Sciences, Fudan University, Shanghai 200032, ChinaAllosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors.https://www.mdpi.com/2218-273X/11/7/929GLP-1Rvirtual screeningallosteric modulatordrug discoverymolecular docking |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Qingtong Zhou Wanjing Guo Antao Dai Xiaoqing Cai Márton Vass Chris de Graaf Wenqing Shui Suwen Zhao Dehua Yang Ming-Wei Wang |
| spellingShingle |
Qingtong Zhou Wanjing Guo Antao Dai Xiaoqing Cai Márton Vass Chris de Graaf Wenqing Shui Suwen Zhao Dehua Yang Ming-Wei Wang Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening Biomolecules GLP-1R virtual screening allosteric modulator drug discovery molecular docking |
| author_facet |
Qingtong Zhou Wanjing Guo Antao Dai Xiaoqing Cai Márton Vass Chris de Graaf Wenqing Shui Suwen Zhao Dehua Yang Ming-Wei Wang |
| author_sort |
Qingtong Zhou |
| title |
Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening |
| title_short |
Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening |
| title_full |
Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening |
| title_fullStr |
Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening |
| title_full_unstemmed |
Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening |
| title_sort |
discovery of novel allosteric modulators targeting an extra-helical binding site of glp-1r using structure- and ligand-based virtual screening |
| publisher |
MDPI AG |
| series |
Biomolecules |
| issn |
2218-273X |
| publishDate |
2021-06-01 |
| description |
Allosteric modulators have emerged with many potential pharmacological advantages as they do not compete the binding of agonist or antagonist to the orthosteric sites but ultimately affect downstream signaling. To identify allosteric modulators targeting an extra-helical binding site of the glucagon-like peptide-1 receptor (GLP-1R) within the membrane environment, the following two computational approaches were applied: structure-based virtual screening with consideration of lipid contacts and ligand-based virtual screening with the maintenance of specific allosteric pocket residue interactions. Verified by radiolabeled ligand binding and cAMP accumulation experiments, two negative allosteric modulators and seven positive allosteric modulators were discovered using structure-based and ligand-based virtual screening methods, respectively. The computational approach presented here could possibly be used to discover allosteric modulators of other G protein-coupled receptors. |
| topic |
GLP-1R virtual screening allosteric modulator drug discovery molecular docking |
| url |
https://www.mdpi.com/2218-273X/11/7/929 |
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