Free-energy reconstructed from the bias-exchange metadynamics simulations of DADLE. Free-energy differences from the lowest energy minimum A are reported in kJ/mol. Representative structures (cluster medoids) for minima A, A′, B, B′, and C are reported in red, pink, dark blue, light blue, and green, respectively. The location on the map of representative, putative bioactive conformations is indicated with a six- or a five-point star for Clusters 1 and 2, respectively.