Outliers in SAR and QSAR: 3. Importance of considering the role of water molecules in protein-ligand interactions and quantitative structure-activity relationship studies.

Abstract

It is frequently mentioned that QSARs have not generally lived up to expectations, especially in cases where high predictability is expected yet failed to deliver satisfactory results. Even though outliers can provide an increased opportunity in drug discovery research, outliers in SAR and QSAR can contort predictions and affect the accuracy if proper attention is not given. The percentages of outliers in QSARs have not changed appreciably over the last decade. In our previous studies, we suggested two possible sources of outliers in SAR and QSAR. In this paper, we suggest an additional possible source of outliers in QSAR. We presented several literature examples that show one or more water molecules that play a critical role in protein-ligand binding interactions as observed in their crystal structures. These examples illustrate that failing to account for the effects of water molecules in protein-ligand interactions could mislead interpretation and possibly yield outliers in SAR and QSAR. Examples include cases where QSAR, considering the role of water molecules in protein-ligand crystal structures, provided deeper insight into the understanding and interpretation of the developed QSAR.