Computational capabilities are rapidly increasing, primarily because of the availability of GPU-based architectures. This creates unprecedented simulative possibilities for the systematic and robust computation of thermodynamic observables, including the free energy of a drug binding to a target. In contrast to calculations of relative binding free energy, which are nowadays widely exploited for drug discovery, we here push the boundary of computing the binding free energy and the potential of mean force. We introduce a novel protocol that leverages enhanced sampling, machine learning, and ad hoc algorithms to limit human intervention, computing time, and free parameters in free energy calculations. We first validate the method on a host-guest system, and then we apply the protocol to glycogen synthase kinase 3 beta, a protein kinase of pharmacological interest. Overall, we obtain a good correlation with experimental values in relative and absolute terms. While we focus on protein-ligand binding, the strategy is of broad applicability to any complex event that can be described with a path collective variable. We systematically discuss key details that influence the final result. The parameters and simulation settings are available at PLUMED-NEST to allow full reproducibility.