TY  - JOUR
T1  - Residence Time Should Be Treated as an Ensemble Property in Molecular Simulation of Drug Binding
A1  - James O'Leary
A1  - Aisling Dunne
A1  - Sean O'Brien
JF  - International Journal of Pharmaceutical Research and Allied Sciences
JO  - Int J Pharm Res Allied Sci
SN  - 2277-3657
Y1  - 2025
VL  - 14
IS  - 1
DO  - 10.51847/3mBy04MLWa
SP  - 152
EP  - 162
N2  - Drug–target residence time is often discussed as though it were a scalar molecular attribute attached to a ligand–protein pair. Molecular simulation increasingly makes that interpretation difficult to sustain. Long-timescale and enhanced-sampling studies show that dissociation can proceed through multiple bound microstates, kinetically distinct exit routes, transition-state configurations, and protein–solvent reorganizations, while the inferred kinetic observable itself depends on sampling strategy, physical Hamiltonian, state definition, and first-passage estimator. This Perspective argues that simulated residence time should therefore be treated as an ensemble property: a macroscopic kinetic summary emerging from a conditional distribution of microscopic trajectories rather than from one privileged dissociation path. The proposal does not deny the utility of a scalar residence time. Instead, it requires that the scalar be interpreted together with evidence for state, pathway, and estimator convergence. The framework separates route discovery from route weighting, distinguishes sampling uncertainty from Hamiltonian uncertainty, and treats agreement with experiment as a validation gate rather than proof that a simulated microscopic mechanism is unique. This ensemble interpretation provides a stricter basis for comparing kinetic simulations, diagnosing failures, and deciding when a residence-time estimate is sufficiently supported for medicinal-chemistry use.
UR  - https://ijpras.com/article/residence-time-should-be-treated-as-an-ensemble-property-in-molecular-simulation-of-drug-binding-6rqm9wn0w8daoca
ER  -