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.