Structure-Based Discovery of Orthosteric Non-Peptide GLP-1R Agonists via Integrated Virtual Screening and Molecular...

Area of Science:

• Medicinal Chemistry
• Computational Drug Discovery
• Pharmacology

Background:

• Orally bioavailable non-peptidomimetic glucagon-like peptide-1 receptor agonists (GLP-1RAs) represent a significant therapeutic advance for type 2 diabetes mellitus (T2DM) and obesity.
• Identifying novel GLP-1RAs requires innovative drug design strategies beyond traditional peptidomimetics.

Purpose of the Study:

• To identify novel non-peptidic GLP-1RAs from natural product libraries using an integrated in silico approach.
• To evaluate the binding affinity, stability, and pharmacokinetic properties of potential GLP-1RA candidates.

Main Methods:

• Screening of over 700,000 compounds from the COCONUT and Marine Natural Products (CMNPD) libraries using shape-based similarity and precision docking against the GLP-1 receptor (PDB ID: 6X1A).
• Binding affinity assessment using molecular mechanics MM-GBSA and validation through 500 ns molecular dynamics (MD) simulations.
• Pharmacokinetic and drug-likeness evaluation using ADMET profiling.

Main Results:

• Twenty final hits were identified, with several compounds (e.g., hits 1, 6, 7, 10) showing potential for novel mechanisms via GLP-1 activity.
• Hits 1, 5, and 9 demonstrated strong, stable interactions with critical active site residues (TRP-203, PHE-381, GLN-221) and favorable pharmacokinetic profiles.
• Hit 9 exhibited the highest binding affinity (ΔG_bind = -102.78 kcal/mol) and desirable ADMET characteristics, surpassing the control compound.

Conclusions:

• The study successfully identified novel non-peptidic GLP-1RA scaffolds from natural product libraries through a robust computational pipeline.
• Hit 9 emerged as a particularly promising candidate for further preclinical development due to its superior binding affinity and drug-like properties.
• This approach highlights the potential of natural products in discovering new therapeutic agents for metabolic diseases mediated by GLP-1.