title: Utility of protein structures in overcoming ADMET-related issues of drug-like compounds.
abstract: 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.
authors.affiliation: Bayer HealthCare AG, Global Drug Discovery, Medicinal Chemistry, Wuppertal, Germany. alexander.hillisch@bayer.com
authors.forename: Friederike
authors.initials: F
authors.lastname: Stoll
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Göller
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillisch
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011506:Proteins