Despite its small size, 3PBA has been identified in two separate fragment screens as an efficient ligand of p38 MAP kinase 1 and leukotriene A4 hydrolase. In the former study, although its binding affinity was found to be greater than 1 mM in an enzyme bioassay, 3BPA has a clearly defined binding mode to the hinge region of the ATP binding site of the kinase (Figure ). While in the latter, the same compound binds near the bottom of the substrate binding cleft of leukotriene A4 hydrolase with sub-mM affinity (Figure ). To investigate the binding of 3BPA in these two environments, we have interfaced GAP with the MCPRO software. MCPRO is a tool for structure-based lead optimization through the use of free energy perturbation (FEP) theory combined with Monte Carlo sampling of protein-ligand binding modes. It has been used for the successful computationally guided design of inhibitors of targets including HIV-1 reverse transcriptase 49 and macrophage migration inhibitory factor, and has recently been applied to the fragment-based design of inhibitors of the Aurora A kinase -TPX2 protein-protein interaction. As we will show, our interface between GAP and MCPRO allows us to perform Monte Carlo simulations of 3BPA in a range of environments, and to compute corrections to the binding free energy that is computed using molecular mechanics force fields.