Toward a First-Principles Understanding of How Cells and Small-Molecule Drugs Work under Native Physiological Conditions

The high clinical failure rate of small-molecule drugs is inarguably attributable to the lack of reliable predictions of chemical structure-efficacy-toxicity relationships that are applicable to native physiological conditions in humans. Existing predictions rely on empirical models of structure-free energy and structure-activity/property relationships derived from equilibrium data that break down under native nonequilibrium, nonlinear dynamic cellular conditions (where noncovalent inter- and intramolecular state transitions are governed strictly by free energy barriers (ΔG^‡)). We have developed a first-principles, physics-based theory that connects the dots between (1) structure and ΔG^‡ via the desolvation and resolvation costs of entering and exiting noncovalent intra- and intermolecular states, respectively; (2) ΔG^‡, PK, and dynamic fractional drug-target and off-target occupancy (denoted as γ(t)); and (3) γ(t) and pharmaco- and toxicodynamic behaviors. Here, we overview our theory, together with its reduction to practice and potential to facilitate greatly improved predictions of human-relevant chemical structure-efficacy/toxicity relationships.