Dataset Information

PdCSM-GPCR: predicting potent GPCR ligands with graph-based signatures.

ABSTRACT:

Motivation

G 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.

Results

Bioactivity 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 implementation

pdCSM-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 information

Supplementary data are available at Bioinformatics Advances online.

SUBMITTER: Velloso JPL

PROVIDER: S-EPMC8651072 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The rapid growth of structural information for G-protein-coupled receptors (GPCRs) has led to a greater understanding of their structure, function, selectivity, and ligand binding. Although novel ligands have been identified using methods such as virtual screening, computationally driven lead optimization has been possible only in isolated cases because of challenges associated with predicting binding free energies for related compounds. Here, we provide a systematic characterization of the performance of free-energy perturbation (FEP) calculations to predict relative binding free energies of congeneric ligands binding to GPCR targets using a consistent protocol and no adjustable parameters. Using the FEP+ package, first we validated the protocol, which includes a full lipid bilayer and explicit solvent, by predicting the binding affinity for a total of 45 different ligands across four different GPCRs (adenosine A2AAR, β1 adrenergic, CXCR4 chemokine, and δ opioid receptors). Comparison with experimental binding affinity measurements revealed a highly predictive ranking correlation (average spearman ρ = 0.55) and low root-mean-square error (0.80 kcal/mol). Next, we applied FEP+ in a prospective project, where we predicted the affinity of novel, potent adenosine A2A receptor (A2AR) antagonists. Four novel compounds were synthesized and tested in a radioligand displacement assay, yielding affinity values in the nanomolar range. The affinity of two out of the four novel ligands (plus three previously reported compounds) was correctly predicted (within 1 kcal/mol), including one compound with approximately a tenfold increase in affinity compared to the starting compound. Detailed analyses of the simulations underlying the predictions provided insights into the structural basis for the two cases where the affinity was overpredicted. Taken together, these results establish a protocol for systematically applying FEP+ to GPCRs and provide guidelines for identifying potent molecules in drug discovery lead optimization projects.