H-REMD simulations were performed using the REST2 protocol implemented in the Plumed 2.8.2 plugin for GROMACS 2022.05 . We used 12 replicas and exchanges were attempted every 100 steps. Unless noted otherwise, scaling factors were distributed between 1 and 0.125 using the quadratic scheme. We found that REST2 performed poorly for lorlatinib due to the ring tension, and therefore employed an adapted version of the protocol for this compound, in which also the bond-angle parameters were scaled. This can be seen as a special case of generalized REST (gREST) . We will refer to this protocol as bond-angle-REST2, and compare it to standard REST2 in Figure in the Supporting Information.