Journal
PHARMACEUTICAL RESEARCH
Volume 32, Issue 3, Pages 986-1001Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-014-1511-3
Keywords
cytochrome P450; ensemble docking; protein flexibility; pseudo-receptor modeling; quantitative structure-activity relationship; site of metabolism prediction; SMARTCyp
Funding
- National Institutes of Health [GM092855]
- Department of Education Graduate Assistantship for Areas of National Need (GAANN) Fellowship
Ask authors/readers for more resources
Predicting atoms in a potential drug compound that are susceptible to oxidation by cytochrome P450 (CYP) enzymes is of great interest to the pharmaceutical community. We aimed to develop a computational approach combining ligand- and structure-based design principles to accurately predict sites of metabolism (SoMs) in a series of CYP2C9 substrates. We employed the reactivity model, SMARTCyp, ensemble docking, and pseudo-receptor modeling based on quantitative structure-activity relationships (QSAR) to account for influences of both the inherent reactivity of each atom and the physical structure of the CYP2C9 binding site. We tested ligand-based prediction alone (i.e. SMARTCyp), structure-based prediction alone (i.e. AutoDock Vina docking), the linear combination of the SMARTCYP and docking scores, and finally a pseudo-receptor QSAR model based on the docked compounds in combination with SMARTCyp. We found that by using the latter combined approach we were able to accurately predict 88% and 96% of the true SoMs, within the top-1 and top-2 predictions, respectively. We have outlined a novel combination approach for accurately predicting SoMs in CYP2C9 ligands. We believe that this method may be applied to other CYP2C9 ligands as well as to other CYP systems.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available