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

Abstract

We previously reported the successful design, synthesis and testing of the prototype opioid painkiller NFEPP that does not elicit adverse side effects. Uniquely, this design 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 a novel stochastic model of GPCR function that includes intracellular dissociation of G-protein subunits and modulation of plasma membrane calcium channels associated with parameters of inflamed and healthy tissue (pH, radicals). The model is validated against in vitro experimental data for NFEPP and fentanyl ligands at different pH values. We found markedly reduced calcium channel inhibition induced by NFEPP at normal pH compared to lower pH, in contrast to the effect of fentanyl, and enhanced constitutive G-protein activation but lower probability of ligand binding with increasing radical concentrations. By means of molecular dynamics simulations, we also assessed qualitative changes of reaction rates due to additional disulfide bridges inside the GPCR binding pocket. 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.

Nexus Between Economic Efficiency, Healthcare, and Environmental Expenditures: A Perspective of BRI Countries

“…Precisely, economically efficient countries can increase the healthcare expenditures, because they better utilize their given inputs or resources, and have the potential to constraint their budgets in order to maintain the public health standards. BRI countries are needed to expand healthcare expenditures, because they are facing several diseases such as typhoid, depression, anxiety, obesity, cancer, HIV aids, and so on (68)(69)(70). In addition, the coefficient of the joint effect of environmental expenditures and economic efficiency have positive effects but lower magnitudes.…”