There has been an explosion of structural information for pharmaceutical compounds bound to biol. targets, but the conformations and dynamics of compounds free in solution are poorly characterized. Yet, the unbound state of compounds is important to better understand their recognition by biol. macromols., including the much debated conformational intramol. reorganization energy of compounds upon binding (ΔEReorg). This also raises questions about the suitability of available aqueous solvation models. These questions were addressed with mol. dynamics (MD) simulations of 26 selected diverse compounds unbound in explicit solvent. The MD-simulated free compounds are compared to conformers generated with ad hoc sampling in vacuo or with implicit generalized Born (GB) aqueous solvation models. The GB conformational models depart from those obtained in explicit solvent, and suffer from conformational collapse. Thus, many low energy conformers obtained with GB may be unsuitable representations of the unbound state, calling for further development in this area. The notion of conformational pre-organization for binding was investigated by comparing the MD-simulated compounds to their bioactive X-ray structure. The ligand-protein complexes were also simulated in explicit solvent to estimate ΔEReorg. This approach yielded low to moderate values of ΔEReorg for 18 out of 26 compounds For three particularly polar compounds, ΔEReorg was substantial (≥15 kcal/mol). Those large ΔEReorg values correspond to a redistribution of electrostatic interactions upon binding. Overall, the study indicates how computational work will allow visualising and understanding the unbound state of compounds