Molecular Probe Conformational Generation in SMARTpy. The initial method for conformer searching implemented in the SMART package was a simple torsional search algorithm that rejected moves based on Van der Waals overlaps with the structure. This method performed well for acyclic probes with freely rotatable bonds, but conformational searching for macrocycles was not possible using this method. Macrocyclic structures are a known limitation of torsional algorithms as rotating one bond along a macrocycle causes multiple other bonds to MacroModel conformational searching employs a version of the ConfGen algorithm disclosed by Watts et. al. to expand applicability and speed up conformer searching. ConfGen employs a template-based method where substructures of the molecule of interest are matched to precomputed templates of conformer ensembles. Inspired by the format of the ConfGen algorithm, a similar approach was employed in SMARTpy.