Below we propose the most efficient way to perform ABFE calculations at large scale such that reliability as well as computational efficiency is ensured. First of all, an initial screening of all complexes should be done using our recommended protocol (whether standard or minimum). Thereafter, only the subset of compounds that do not fulfil one or both the above criteria of reliability should be considered for further extended sets of simulations. The extended simulations should be performed in steps, adjusting one parameter at a time in a set order, and filtering out the compounds that fulfil the criteria at each step. This is to ensure that the additional computational costs are minimised.