p38 Mitogen-Activated Protein Kinase p38 MAP kinase is a pharmaceutically relevant target since it helps regulate the production of proinflammatory cytokines. Its inhibition is a possible strategy for the treatment of several inflammatory diseases. Its inhibitor BIRB796 was structurally characterized via X-ray crystallography by Pargellis et al. and kinetically characterized by Regan et al. via competition assay with a fluoroprobe (see Supporting Information for ligand structures). The RAMD egress pathways as well as the path CV with a representative iMetaD path are shown in Figure . In Figure we report the correlation of RAMD with experimental residence time. RAMD can rank-order the compounds with acceptable accuracy (Figure ). When iMetaD is performed using the main egress path from RAMD, we can see that the absolute residence time values are recovered while the rank ordering is maintained (Figure , Table ). This comes with a computational cost that ranges from several hundred nanoseconds to 3 microseconds. On modern GPUs (e.g. NVIDIA L4) this takes approximately 100 -300 GPU hours which can be trivially parallelized over the 20 iMetaD replicas. Interestingly, Lig3 is the compound that shows the highest discrepancy from the experimental value. This is also associated with the highest rate of unproductive runs (20%) which in general are considered a strong sign of emerging orthogonal degrees of freedom with respect to the CVs used in iMetaD. Since our implementation of iMetaD accelerates only the motion of the ligand with respect to the protein and the ligand conformation, examples of these emerging orthogonal degrees of freedom may be protein rearrangements along the egress path or water sampling. For those cases one may be less confident of the results and, from this point of view, this represents a useful confidence metric not present, for example, in RAMD.