title: Structure-based ligand design to overcome CYP inhibition in drug discovery projects.
abstract: Cytochrome P450 (CYP) enzymes are key players in xenobiotic metabolism, and inhibition of CYPs can therefore result in unwanted drug-drug interactions. Within drug discovery, CYP inhibition can cause delays in the progression of candidate drugs, or even premature closure of projects. During the past decade, a massive effort in the pharmaceutical industry and academic research has produced a wealth of structural information in the CYP field. In this short review, we will describe how structure-based approaches can be used in the pharmaceutical industry to work away from CYP inhibition, with a focus on the opportunities and challenges. We will show two examples from our own work where structural information on CYP2C9 and CYP3A4 inhibitor complexes have been successfully exploited in ongoing drug discovery projects.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg S-405 30, Sweden. Electronic address: gisela.branden@gu.se.
authors.forename: Gisela
authors.initials: G
authors.lastname: Brändén
authors.affiliation: Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Sjögren
authors.affiliation: CVMD iMed, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Volker
authors.initials: V
authors.lastname: Schnecke
authors.affiliation: Discovery Sciences, AstraZeneca R&D Mölndal, Mölndal S-431 83, Sweden.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Xue
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D008024:Ligands; D003577:Cytochrome P-450 Enzyme System