GLP1R PAM virtual screen. C1 Analogs.

C-1 comes from a structure‐based virtual screening of 5689 compounds from the ZINC database. about 60 compounds among the GLP1R predicted active molecules show > 70% similarity with C-1.

Some exemplars below. 

C-1 similar compouds show activity in several ChEMBL phenotypes. 

Literature references

Br J Pharmacol. 2022 Feb; 179(4): 511–525. doi: 10.1111/bph.15446

Non‐peptide agonists and positive allosteric modulators of glucagon‐like peptide‐1 receptors: Alternative approaches for treatment of Type 2 diabetes

Faisal Malik 1 and Zhijun Li         1

Abstract

Glucagon‐like peptide‐1 (GLP‐1) receptors belong to the pharmaceutically important Class B family of GPCRs and are involved in many biologically significant signalling pathways. Its incretin peptide ligand GLP‐1 analogues are effective treatments for Type 2 diabetes. Although developing non‐peptide low MW drugs targeting GLP‐1 receptors remains elusive, considerable progress has been made in discovering non‐peptide agonists and positive allosteric modulators (PAMs) of GLP‐1 receptors with demonstrated efficacy. Many of these compounds induce biased signalling in GLP‐1 receptor‐mediated functional pathways. High‐quality structures of GLP‐1 receptors in both inactive and active states have been reported, revealing detailed molecular interactions between GLP‐1 receptors and non‐peptide agonists or PAMs. These progresses raise the exciting possibility of developing non‐peptide drugs of GLP‐1 receptors as alternative treatments for Type 2 diabetes. The insight into the interactions between the receptor and the non‐peptide ligand is also useful for developing non‐peptide ligands targeting other Class B GPCRs.

3.2.2. Compound M_4 and C‐1

Following the publication of the structure of two Class B GPCRs, the CRF1 receptor (PDB ID: 4K5Y) and the glucagon receptor (PDB ID: 4L6R), our group constructed the homology models of human GLP‐1 receptors, based on those two crystal structures and carried out structure‐based virtual screening of 5689 compounds from the ZINC database (Redij, Chaudhari, et al., 2019). These compounds have similar physicochemical properties to those of potential low MW agonists of GLP‐1 receptors and were identified through ligand‐based similarity search. Eight top‐ranked compounds from virtual screening were selected and evaluated using the GLP‐1 receptor‐dependent luciferase reporter system. Two compounds were confirmed to activate human GLP‐1 receptors in a dose‐dependent manner and one synergized with GLP‐1 to stimulate GLP‐1 receptor activity, compound 17 (M_4) (Figure 3, [17]). Using in vitro insulin secretion assay in INS‐1832/13 cells, compound M_4 induced glucose‐dependent insulin secretion.

When the cryo‐EM structure of GLP‐1 receptors at the active state became available (Y. Zhang et al., 2017), we carried out another round of structure‐based screening studies using this structure and identified another compound as a PAM for GLP‐1 receptors, compound 18 (C‐1) (Figure 3, [18]) (Redij, Ma, et al., 2019). Using the same GLP‐1 receptor‐dependent luciferase reporter system, compound C‐1 activates human GLP‐1 receptors in a dose‐dependent manner. When combined with GLP‐1, C‐1 improves GLP‐1’s affinity and efficacy to human GLP‐1 receptors. Using in vitro insulin secretion assay in INS‐1832/13 cells, compound C‐1 (9.7 μM), induced insulin secretion at the similar level as that of GLP‐1 (181 nM). Combined with GLP‐1, C‐1 again showed the synergistic effect in stimulating insulin secretion. Despite its modest activity, this compound demonstrates favourable drug‐like properties. For instance, with the molecular weight of 399, this compound represents one of the smallest known PAMs for the GLP‐1 receptor.

J Comput Aided Mol Des. 2019 Nov;33(11):973-981. PMID: 31758355. DOI: 10.1007/s10822-019-00254-4

Discovery of a potential positive allosteric modulator of glucagon-like peptide 1 receptor through virtual screening and experimental study

Tejashree Redij ¹, Jian Ma ², Zhiyu Li ³, Xianxin Hua ², Zhijun Li ^4 5

Abstract

The Glucagon-like peptide 1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes and GLP-1R agonist-based therapies represent an effective approach which results in several GLP-1 analog drugs. However, the development of nonpeptidic agonist drugs targeting GLP-1R remains unsuccessful. A promising strategy aims to develop orally bioavailable, small-molecule positive allosteric modulators of GLP1-1R. Taking advantage of the recently reported cryo-EM structure of GLP-1R at its active state, we have performed structure-based screening studies which include potential allosteric binding site prediction and in silico screening of drug-like compounds, and conducted in vitro testing and site-specific mutagenesis studies. One compound with low molecular weight was confirmed as a positive allosteric modulator of GLP-1R as it enhances GLP-1’s affinity and efficacy to human GLP-1R in a dose dependent manner. This compound also stimulates insulin secretion synergistically with GLP-1. With the molecular weight of 399, this compound represents one of the smallest known GLP-1R PAMs, and demonstrates other favorable drug-like properties. Site-specific mutagenesis studies confirmed that the binding site of this compound partially overlaps with that of a known antagonist in the transmembrane domain. These results demonstrate that structure-based approach is useful for discovering nonpeptidic allosteric modulators of GLP-1R and the compound reported here is valuable for further drug development.