Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers

Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms action these PEs are complex, but, typically, when used for oral administration, they transiently induce alteration trans- and paracellular pathways, including increased solubilization membrane fluidity, or opening tight junctions. To elucidate mechanistic details, it is important to understand aggregation behavior not only themselves but also other molecules already present in intestine. Aggregation processes depend critically on, among factors, charge state ionizable chemical groups, which affected by pH system. In this study, we explicit-pH coarse-grained molecular dynamics simulations investigate dependence two commonly PEs—caprate SNAC—together with components fasted- fed-state simulated intestinal fluids. We validate a topology bile salt taurocholate suitable Martini3 force-field. Our results indicate an number free as function system each combination FaSSIF/FeSSIF PEs. addition, there differences between caprate SNAC, rationalized based on their different structures critical micelle concentrations.