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 consists of in silico simulations performed at the atomistic and molecular systems levels, versus empirical models fit to in vitro data under the classical paradigm.

当前的早期和临床前药物发现植根于几十年前的经验原则，描述了平衡条件下的无结构能量和结构-功能关系，而平衡条件下在体内条件下经常会分解。对疗效和毒性的改进预测取决于向体内相关原理的范式转变，该原理描述了细胞系统的真正非平衡/非线性动态 (NLD) 特性。在这里，我们概述了一个整体的、与体内相关的第一原理理论（“生物动力学”），其中细胞功能/功能障碍和药物/毒物动力学效应被认为是由共价和非共价自由能源驱动的多分子系统的紧急行为。将生物动力学理论付诸实践包括在原子和分子系统水平上进行的计算机模拟，