Drug design is a comprehensive interdisciplinary field, and the integration of disciplines such as molecular modeling, spectroscopy, and in vitro biochemical methods was demonstrated to be a very effective research tool. Information provided by the three-dimensional structure of the receptor-inhibitor complex can be used to explain the results of the affinity data and guide the computer-aided search for improved inhibitors. It has been demonstrated that the lack of reproducible HIV PR bioactivity data severely hampers theoretical advancement of new HIV PR drugs. This is likely the case for other diseases as well. The authors recommend that experimental binding free energies obtained from thermal titration calorimetry experiments be used as the standard biophysical data to which theoretical models are gauged. It is clear that computer-aided rational drug design provides essential molecular insight into drug-host interactions that are not easily and fully accessible from conventional experimental techniques on their own.