Rational design of therapeutic peptides using physics-based molecular dynamics simulations
Abstract: Peptides are sustainable alternatives to conventional therapeutics for G protein-coupled receptor (GPCR) linked disorders, promising biocompatible and tailorable next-generation therapeutics for metabolic disorders including type-2 diabetes, as agonists of the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R). However, single agonist peptides activating GLP-1R to stimulate insulin secretion also suppress obesity-linked glucagon release. Hence, bioactive peptides co-targeting GCGR and GLP-1R may remediate the blood glucose and fatty acid metabolism imbalance, tackling both diabetes and obesity to supersede current mono-agonist therapy. Here we design and model optimised peptide sequences starting from peptide sequences derived from earlier phage-displayed library screening, identifying those with predicted molecular binding profiles for dual agonism of GCGR and GLP-1R. We derive design rules from extensive molecular dynamics simulations based on peptide–receptor binding. Our newly designed co-agonist peptide exhibits improved coupled binding affinity for GCGR and GLP-1R relative to endogenous ligands, which may provide superior glycaemic and weight loss control.
Event Details: https://www.ul.ie/node/85169
UL PHYSICS DEPARTMENT RESEARCH DAY – 19th May 2023
The event showcased the breadth of research conducted in the Department and was an excellent opportunity for networking and engaging with the Physics community at UL.
Also affiliated with
- Synthesis and Solid State Pharmaceutical Centre