Altered residence time as a cause of drug resistance

Drug-target residence time is a crucial determinant of pharmacological efficacy, complementing traditional equilibrium affinity measures. Variations in residence time influence drug selectivity, therapeutic windows, and resistance development, yet its molecular underpinnings remain incompletely understood. Here we review factors governing residence time, including kinetic parameters and structural influences, and examine how mutations can alter dissociation rates to confer drug resistance. We highlight recent advances in experimental and computational methods, such as molecular dynamics simulations, that enable prediction and rational design of compounds with optimized residence times. These insights underscore the importance of incorporating kinetic considerations into drug discovery to improve efficacy and overcome resistance. Our findings suggest that optimizing residence time offers a promising strategy to enhance therapeutic outcomes for diverse diseases.