Stavros N Politis, Paolo Colombo, Gaia Colombo, Dimitrios M Rekkas
Design of experiments (DoE) in pharmaceutical development
Drug development and industrial pharmacy
starting universal concept entropy production large number new results obtained wealth novel thermodynamic kinetic molecular mechanistic insights provided coupling oxidation atp synthesis vital process oxidative phosphorylation ox phos total dissipation ox phos succinate respiratory substrate quantified measurements partitioning elementary components atp synthesis leak slip losses evaluated first time thermodynamic efficiency coupled process calculated data shown agree well linear nonequilibrium thermodynamic calculations equations po ratio based total oxygen consumed extra oxygen consumed derived first principles source basal state 4 mitochondrial respiration postulated molecular mechanistic considerations based naths twoion theory energy coupling within torsional mechanism energy transduction atp synthesis degree coupling q oxidation atp synthesis determined experimental data irreversible thermodynamics analysis optimality biological free energy converters explored considerable detail based standard biothermodynamic approach ii new biothermokinetic approach developed work effective solution shown arise consideration molecular aspects naths theory formulated new experimental data state 4 uncouplers redox inhibitors ox phos respiratory control physiological state 3 adp uncouplers presented experimental observations shown incompatible mitchells chemiosmotic theory novel scheme coupling based naths twoion theory energy coupling within torsional mechanism proposed shown explain data also pass test consistency thermodynamics taking us beyond chemiosmotic theory concluded twenty years since first proposal naths torsional mechanism energy transduction atp synthesis well poised catalyze progress experimental theoretical research interdisciplinary field