Outliers in SAR and QSAR: 2. Is a flexible binding site a possible source of outliers?

Structure-activity relationship (SAR) and/or quantitative structure-activity relationship (QSAR) studies play an important role in a lead optimization of drug discovery research. When there is a lack of ligand-bound protein structural information, one of the assumptions in SAR and QSAR studies is that similar analogs bind to the same binding site in a similar binding mode. In such studies, outliers have often been observed, especially in QSAR. However, most of these studies have focused their attention on the development of QSAR and left outliers unattended. We searched 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 showed the possibility of conformational changes in a flexible binding site as one possible source of outliers.