In this work we propose methodological advances that enable efficient absolute binding free energy calculations with an accuracy on par with relative free energy calculations. We demonstrate the generality of the protocol across multiple pharmaceutically relevant tar-gets in a large scale study. Our approach enables the incorporation of both holo and apo structural information for reliable affinity predictions. The key structural determinants of binding can be as small as a single rotamer change between the apo and holo states and appropriate sampling of such determinants can be computationally demanding. When multiple alternative apo structures exist, absolute binding free energy calculations can be used to identify the most likely candidate for a prospective study.