Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening
Qingtong Zhou,
Wanjing Guo,
Antao Dai,
Xiaoqing Cai,
Márton Vass,
Chris de Graaf,
Wenqing Shui,
Suwen Zhao,
Dehua Yang,
Ming-Wei Wang
Affiliations
Qingtong Zhou
School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Wanjing Guo
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Antao Dai
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xiaoqing Cai
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Márton Vass
Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands
Chris de Graaf
Amsterdam Institute for Molecules, Medicines and Systems, Division of Medicinal Chemistry, Faculty of Sciences, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands
Wenqing Shui
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Suwen Zhao
iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Dehua Yang
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Ming-Wei Wang
School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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.
