Repository: Freie Universität Berlin, Math Department

Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design

Thies, Arne and Sunkara, Vikram and Ray, Sourav and Wulkow, Hanna and Özgür Celik, M. and Yergöz, Fatih and Schütte, Christof and Stein, Christoph and Weber, Marcus and Winkelmann, Stefanie (2023) Modelling altered signalling of G-protein coupled receptors in inflamed environment to advance drug design. Scientific Reports, 13 (1). p. 607.

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We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. The design process of NFEPP was based on mathematical modelling of extracellular interactions between G-protein coupled receptors (GPCRs) and ligands, recognizing that GPCRs function differently under pathological versus healthy conditions. We now present an additional and novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels and their dependence on parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for the ligands NFEPP and fentanyl at different pH values and radical concentrations. We observe markedly reduced binding affinity and calcium channel inhibition for NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl. For increasing radical concentrations, we find enhanced constitutive G-protein activation but reduced ligand binding affinity. Assessing the different effects, the results suggest that, compared to radicals, low pH is a more important determinant of overall GPCR function in an inflamed environment. Future drug design efforts should take this into account.

Item Type:Article
Subjects:Mathematical and Computer Sciences
Mathematical and Computer Sciences > Mathematics
Mathematical and Computer Sciences > Mathematics > Applied Mathematics
Divisions:Department of Mathematics and Computer Science > Institute of Mathematics
ID Code:2957
Deposited By: Monika Drueck
Deposited On:20 Apr 2023 10:22
Last Modified:02 Feb 2024 13:31

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