Simple thermodynamic model of unassisted proton shuttle uncoupling and prediction of activity from calculated speciation, lipophilicity, and molecular geometry

► A physiological model of uncoupling by proton shuttles was developed. ► It allows activity to be predicted from easily-estimated physicochemical properties. ► It effectively discriminates actives from related compounds with little to no activity. ► The model was used to screen a library of naturally-occurring compounds in-silico. ► The model was used to formulate principles of design for optimized activity.