Free energy calculations have become part of the standard repertoire of computationalbiochemical research due to their widespread applicability, reaching from the predictionof binding affinities of small drug-candidate compounds to the evaluation of relative stabilitiesof large biomacromolecular structures. Probably the most well-known end-point, implicitsolvent free energy method is the Molecular Mechanics Poisson–Boltzmann SurfaceArea (MM-PBSA) approach. MM-PBSA allows analyzing individual energy contributionsby means of a free energy decomposition, which gives additional insights into the energeticsof the investigated system. We shall show its application to HIV-1/HIV-2 proteaseinhibitorand neuraminidase-inhibitor systems. Our calculations agree well withexperiment and provide a detailed understanding of the molecular forces governing bindingand drug resistance that might assist in the design of efficient inhibitors against targetprotein.