title: Combining structure- and ligand-based approaches to improve site of metabolism prediction in CYP2C9 substrates.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Kingsley
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Wilson
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Essex
authors.forename: Markus A
authors.initials: MA
authors.lastname: Lill
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D017076:Computer-Aided Design; D065729:Cytochrome P-450 CYP2C9 / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D065729:Cytochrome P-450 CYP2C9