Utility of protein structures in overcoming ADMET-related issues of drug-like compounds

The number of solved X-ray structures of proteins relevant for ADMET processes of drug molecules has increased remarkably over recent years. In principle, this development offers the possibility to complement the quantitative structure–property relationship (QSPR)-dominated repertoire of in silico ADMET methods with protein-structure-based approaches. However, the complex nature and the weak nonspecific ligand-binding properties of ADMET proteins take structural biology methods and current docking programs to the limit. In this review we discuss the utility of protein-structure-based design and docking approaches aimed at overcoming issues related to plasma protein binding, active transport via P-glycoprotein, hERG channel mediated cardiotoxicity and cytochrome P450 inhibition, metabolism and induction.