Structural highlights
Function
[CP2C9_HUMAN] Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan.
Publication Abstract from PubMed
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.
Structure-based ligand design to overcome CYP inhibition in drug discovery projects.,Branden G, Sjogren T, Schnecke V, Xue Y Drug Discov Today. 2014 Jul;19(7):905-911. doi: 10.1016/j.drudis.2014.03.012., Epub 2014 Mar 16. PMID:24642031[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Branden G, Sjogren T, Schnecke V, Xue Y. Structure-based ligand design to overcome CYP inhibition in drug discovery projects. Drug Discov Today. 2014 Jul;19(7):905-911. doi: 10.1016/j.drudis.2014.03.012., Epub 2014 Mar 16. PMID:24642031 doi:http://dx.doi.org/10.1016/j.drudis.2014.03.012
