Dataset Information

Harnessing cyclotides to design and develop novel peptide GPCR ligands.

ABSTRACT: Cyclotides are plant-derived cyclic, disulfide-rich peptides with a unique cyclic cystine knot topology that confers them with remarkable structural stability and resistance to proteolytic degradation. Recently, cyclotides have emerged as promising scaffold molecules for designing peptide-based therapeutics. Here, we provide examples of how engineering cyclotides using molecular grafting may lead to the development of novel peptide ligands of G protein-coupled receptors (GPCRs), today's most exploited drug targets. Integrating bioactive epitopes into stable cyclotide scaffolds can lead to improved pharmacokinetics and oral activity as well as selectivity and high enzymatic stability. We also discuss and highlight the importance of engineered cyclotides as novel tools to study GPCR signaling.

SUBMITTER: Muratspahic E

PROVIDER: S-EPMC8341132 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Harnessing cyclotides to design and develop novel peptide GPCR ligands.

Muratspahić Edin E Koehbach Johannes J Gruber Christian W CW Craik David J DJ

RSC chemical biology 20200722 4

Cyclotides are plant-derived cyclic, disulfide-rich peptides with a unique cyclic cystine knot topology that confers them with remarkable structural stability and resistance to proteolytic degradation. Recently, cyclotides have emerged as promising scaffold molecules for designing peptide-based therapeutics. Here, we provide examples of how engineering cyclotides using molecular grafting may lead to the development of novel peptide ligands of G protein-coupled receptors (GPCRs), today's most exp ...[more]

PMID: 34458757

Similar Datasets

Project description:MotivationG protein-coupled receptors (GPCRs) can selectively bind to many types of ligands, ranging from light-sensitive compounds, ions, hormones, pheromones and neurotransmitters, modulating cell physiology. Considering their role in many essential cellular processes, they are one of the most targeted protein families, with over a third of all approved drugs modulating GPCR signalling. Despite this, the large diversity of receptors and their multipass transmembrane architectures make the identification and development of novel specific, and safe GPCR ligands a challenge. While computational approaches have the potential to assist GPCR drug development, they have presented limited performance and generalization capabilities. Here, we explored the use of graph-based signatures to develop pdCSM-GPCR, a method capable of rapidly and accurately screening potential GPCR ligands.ResultsBioactivity data (IC50, EC50, Ki and Kd) for individual GPCRs were curated. After curation, we used the data for developing predictive models for 36 major GPCR targets, across 4 classes (A, B, C and F). Our models compose the most comprehensive computational resource for GPCR bioactivity prediction to date. Across stratified 10-fold cross-validation and blind tests, our approach achieved Pearson's correlations of up to 0.89, significantly outperforming previous methods. Interpreting our results, we identified common important features of potent GPCRs ligands, which tend to have bicyclic rings, leading to higher levels of aromaticity. We believe pdCSM-GPCR will be an invaluable tool to assist screening efforts, enriching compound libraries and ranking candidates for further experimental validation.Availability and implementationpdCSM-GPCR predictive models and datasets used have been made available via a freely accessible and easy-to-use web server at http://biosig.unimelb.edu.au/pdcsm_gpcr/.Supplementary informationSupplementary data are available at Bioinformatics Advances online.

Dataset Information

Harnessing cyclotides to design and develop novel peptide GPCR ligands.

Publications

Harnessing cyclotides to design and develop novel peptide GPCR ligands.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets