Outliers in SAR and QSAR: is unusual binding mode a possible source of outliers?

A lead optimization is usually carried out by structure-activity relationship (SAR) and/or quantitative structure-activity relationship (QSAR) studies. One of the assumptions in SAR and QSAR studies is that similar analogs bind to the same binding site in a similar binding mode. One often observes that there are outliers, especially in QSAR. However, most QSAR studies are carried out focusing their attention to the development of QSAR and leave the outliers without much attention. We searched a number of ligand-bound X-ray crystal structures from the protein structure database to find evidences that could indicate a possible source of outliers in SAR or QSAR. Our results show that unusual binding mode could be a source of outliers.