Toward in vivo relevant drug design

Current early and preclinical drug discovery are rooted in decades-old empirical principles describing structure-free energy and structure–function relationships under equilibrium conditions that frequently break down under in vivo conditions. Improved prediction of efficacy and toxicity depends on a paradigm shift to in vivo-relevant principles describing the true nonequilibrium/nonlinear dynamic (NLD) nature of cellular systems. Here, we outline a holistic, in vivo-relevant first principles theory (‘Biodynamics’), in which cellular function/dysfunction, and pharmaco-/toxicodynamic effects are considered as emergent behaviors of multimolecular systems powered by covalent and noncovalent free energy sources. The reduction to practice of Biodynamics theory comprises in silico simulations performed at the atomistic and molecular systems levels, versus empirical models fit to in vitro data under the classical paradigm.