Here, we present an overview of the QUBEKit/Sire workflow for molecular modelling (Figure ), and to demonstrate its use, we have chosen as a case study, two sets of non-nucleoside inhibitors of HIV-1 RT (NNRTIs). HIV-1 RT has been extensively studied both computationally and experimentally, and indeed free energy calculations have been crucial to driving improvements in the potency of NNRTI scaffolds (further background and structural details are provided in the Supporting Information). Here, we chose 10 compounds from a series of catechol diethers that incorporate a 7-cyano-2-naphthyl substituent, and 12 compounds comprising indoles, indolizines, and benzofurans from the earlier literature, which we refer to as groups 1 and 2, respectively (full chemical structures are provided in Figure and Table ). We focused on these two datasets as group 1 exemplifies small side chain transformations, whilst group 2 covers a much wider potency range, including heterocyclic substitutions.