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

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.

Prediction of Covid-19 spreading and optimal coordination of counter-measures: From microscopic to macroscopic models to Pareto fronts.

The Covid-19 disease has caused a world-wide pandemic with more than 60 million positive cases and more than 1.4 million deaths by the end of November 2020. As long as effective medical treatment and vaccination are not available, non-pharmaceutical interventions such as social distancing, self-isolation and quarantine as well as far-reaching shutdowns of economic activity and public life are the only available strategies to prevent the virus from spreading. These interventions must meet conflicting requirements where some objectives, like the minimization of disease-related deaths or the impact on health systems, demand for stronger counter-measures, while others, such as social and economic costs, call for weaker counter-measures. Therefore, finding the optimal compromise of counter-measures requires the solution of a multi-objective optimization problem that is based on accurate prediction of future infection spreading for all combinations of counter-measures under consideration. We present a strategy for construction and solution of such a multi-objective optimization problem with real-world applicability. The strategy is based on a micro-model allowing for accurate prediction via a realistic combination of person-centric data-driven human mobility and behavior, stochastic infection models and disease progression models including micro-level inclusion of governmental intervention strategies. For this micro-model, a surrogate macro-model is constructed and validated that is much less computationally expensive and can therefore be used in the core of a numerical solver for the multi-objective optimization problem. The resulting set of optimal compromises between counter-measures (Pareto front) is discussed and its meaning for policy decisions is outlined.