The Protein Data Bank (PDB) reports 'model' structures as the ligand conformations found in the presence of biomacromolecules such as proteins (i.e., bioactive conformations). PDB also reports "ideal" structures to represent a chemically reasonable, idealized structure of the ligand that is optimized to ensure correct bond lengths, bond angles, and stereochemistry. The "ideal" structure is not explicitly meant to be the global minimum; its purpose is to serve as a high-quality, chemically valid model for applications such as docking, visualization, and further computational studies. Our protocol begins with the idea that the "model" and "ideal" structures correspond to two different energetically low-lying structures. Thus, after ensuring "ideal" and "model" structures for each ligand that represent different conformations, starting with an "ideal" structure (one of the minima) and finding "model" structure (another of the minima) with conformer generation process would indicate the success of the algorithm. To assess the true performance of a conformer generation algorithm, we have considered the following scenarios and eliminated most structures according to the criteria defined in each scenario (Figure ). Scenario 1: The "ideal" and "model" structures of a ligand may correspond to the same conformation (minimum). If this is the case, QM optimization of "ideal" structure will already yield to the same structure with QM optimized "model" structure. Including these structures in conformer generation process would bring additional (un-realistic) success. Thus, we have excluded such cases by comparing the RMSD of heavy atoms of "ideal" and "model" structures. We rejected structures with RMSD ≤ 2Å (ideal to model). By applying this criterion, we have also avoided the cumbersome QM optimization of thousands of ligands.