Estrogen receptor alpha (ERα) systems have been studied by multiple groups for scaffold hopping transformation and were therefore an interesting next test system for SepTop. The transformations involve ring extensions; here, in particular, the key ring change is a transformation from a five to a six-membered ring (Figure ). These scaffold hopping transformations fall outside the scope of regular RBFE, although they can be calculated using a softbond potential, 14 additional restraints, or the alchemical transfer method. Here, we wanted to investigate the performance of SepTop on challenging transformations like these and compare results with other methods.