The high cost required for a reliable sampling of any alchemical state, quantified in at least 300 ns for the BRD4(I)-ODR system whether using HREM or MD replicates, has a significant impact on the computational pipelines in drug-receptor binding free energy calculation using the well established FEP approach. Assuming 30 to 40 λ points in a standard FEP calculations of the bound state involving a relatively bulky ligand such as ODR implies that than no less of 10 µs of simulation time is needed for a FEP evaluation. On a high-end heterogeneous architectures such as the Leonardo cluster, recently deployed by the CINECA italian HPC consortium, a single FEP binding free energy calculation for a complex with 50k-60k atoms using GROMACS would engage for 24 hours more than 60 nodes (each node has 4 Nvida A100 GPUS and 32 cores Intel Xeon)