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Exploration of natural compounds as potential negative allosteric modulators of glucagon-like peptide-1 receptor through molecular docking and dynamics simulation coupled with MM-GBSA binding energy calculations

Department of Molecular Biology and Genetics, Istanbul AREL University, Istanbul, Türkiye

Received: 12 August 2025 Accepted: 4 October 2025

Abstract:

The glucagon-like peptide-1 receptor (GLP-1R), a class B G protein-coupled receptor (GPCR), plays an essential role in regulating blood sugar and is a validated target for treating type 2 diabetes mellitus (T2DM) and obesity. The importance of negative allosteric modulators (NAMs) of GLP-1R—especially those derived from natural compounds—is an emerging and relatively underexplored area in pharmacology. This study aims to identify new natural product-derived GLP-1R NAMs through an integrated computational approach. Molecular docking was conducted on 100 natural compounds, including phenolics, flavonoids, alkaloids, anthraquinones, and terpenoids, targeting the allosteric site of GLP-1R. The top candidates with favorable docking scores were further examined with 200 ns molecular dynamics (MD) simulations to assess their binding stability. MM-GBSA calculations estimated the binding free energy of the receptor–ligand complexes. Two natural compounds, strictinin and verbascoside, demonstrated stable binding modes with Glide XP docking scores of − 8.41 and − 8.17 kcal/mol, respectively, along with the corresponding MM-GBSA binding energies of − 65.8 ± 4.2 and − 61.3 ± 5.7 kcal/mol. These results are comparable to the reference NAM, PF-06372222, which had Glide XP docking and MM-GBSA binding energy scores of –6.68 and –58.9 ± 6.1 kcal/mol, respectively. By highlighting the potential of bioactive plant metabolites to allosterically modulate GLP-1R function, these findings suggest their promise as scaffolds for developing new GLP-1R-targeted therapies.

Keywords: GLP-1R; Negative allosteric modulators; Natural products; Molecular docking; Molecular dynamics simulation; MM-GBSA

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04431-8

Chemical Papers 80 (1) 821–836 (2026)

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