Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening

Abstract

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.

Novel anti-Acanthamoeba effects elicited by a repurposed poly (ADP-ribose) polymerase inhibitor AZ9482

“…To identify potential inhibitors targeting A. castellanii PARPs, we first constructed a homology model of a representative A. castellanii PARP (UniProt accession code: L8GH34) based on the X-ray structure of the PARP1 catalytic domain in complex with the inhibitor olaparib (PDB code: 7KK4). Subsequently, we performed virtual screening of an approved drug library ( Ryan et al., 2021 ; Zhou et al., 2021 ), using both rigid docking (Glide SP and XP protocols) and binding free energy estimation. The former was utilized to isolate these docking pose of best docking score, while the latter further relaxed the predicted ligand-PARP1 complex and calculated the binding free energy by Prime MM-GBSA.…”

Small molecule allosteric modulation of the adenosine A1 receptor

“…Such structural determination has provided key insights into allosteric binding across various GPCRs, which in turns aids the discovery of new allosteric modulators using the structure-based drug discovery (SBDD) approach. Several SBDD studies have successfully employed to find new allosteric modulators for GPCRs, including M2 muscarinic acetylcholine receptors ( 144 , 145 ), glucagon-like peptide 1 receptor ( 146 – 148 ), metabotropic glutamate receptor 5 ( 149 ), and proton-sensing receptors GPR68 and GPR65 ( 150 ). These studies demonstrate the power of SBDD to identify new allosteric modulators for GPCRs, paving the way for the development of novel therapeutics with improved selectivity and reduced side effects.…”