Assessment of GPCR ligands Diversity Using Molecular Properties-Based Functional Radars and Fragment Analysis

poster · 13 years ago
by Stéphane Marcel, Ismail Ijjaali, François Petitet, Benjamin Morlon, Elodie Dubus, Dominique Neaud (Aureus Pharma)
Calculator Plugins (logP logD pKa etc...) Fragmenter

By collecting chemical structures of ligands, associated targets with all reported in vitro and in vivo pharmacological responses from the literature, we have built a GPCR knowledgebase. This resource could be used for assessing GPCR-associated pharmacological space.

Datasets have been extracted from this knowledgebase, and then filters have been applied. Only non peptide compounds, tested on GPCR wild type targets, with biological activities (EC50, IC50 and Ki) obtained in binding or second messenger protocols were considered. Depending on the target family, activity thresholds have been set, at 10, 100 or 200 nM. Topological molecular descriptors have been calculated using Calculator™ (ChemAxon) for each unique 2D structure. Each molecular dataset addresses a given GPCR class, superfamily, family or receptor type. Analysis carried out includes comparison of active vs inactive and selective vs non selective compounds.

Functional radars have been used as graphic representations of the GPCR-associated pharmacological space to analyze, potency, specificity and selectivity. These representation of pharmacological spaces combined with chemical fragment occurrence –determined by using Fragmenter™ (ChemAxon) provides a powerful strategy to design focused libraries and improve lead profiling.