title: Discriminant and quantitative PLS analysis of competitive CYP2C9 inhibitors versus non-inhibitors using alignment independent GRIND descriptors.
abstract: This study describes the use of alignment-independent descriptors for obtaining qualitative and quantitative predictions of the competitive inhibition of CYP2C9 on a serie of highly structurally diverse compounds. This was accomplished by calculating alignment independent descriptors in ALMOND. These GRid INdependent Descriptors (GRIND) represent the most important GRID-interactions as a function of the distance instead of the actual position of each grid-point. The experimental data was determined under uniform conditions. The inhibitor data set consists of 35 structurally diverse competitive stereospecific inhibitors of the cytochrome P450 2C9 and the non -inhibitor data set of 46 compounds. In a PLS discriminant analysis 21 inhibitors and 21 non-inhibitors (1 and 0 as activities) were analyzed using the ALMOND program obtaining a model with an r2 of 0.74 and a cross-validation value (q2) of 0.64. The model was externally validated with 39 compounds (14 inhibitors/25 non-inhibitors). 74% of the compounds were correctly predicted and an additional 13% was assigned to a borderline cluster. Thereafter, a model for quantitative predictions was generated by a PLS analysis of the GRIND descriptors using the experimental Ki-value for 21 of the competitive inhibitors (r2 = 0.77, q2 = 0.60). The model was externally validated using 12 compounds and predicted 11 out of 12 of the Ki-values within 0.5 log units. The discriminant model will be useful in screening for CYP2C9 inhibitors from large compound collections. The 3D-QSAR model will be used during lead optimization to avoid chemistry that result in inhibition of CYP2C9.
authors.affiliation: Department of Organic Pharmaceutical Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden. Lovisa.Afzelius@astrazeneca.com
authors.forename: Lovisa
authors.initials: L
authors.lastname: Afzelius
authors.forename: Collen M
authors.initials: CM
authors.lastname: Masimirembwa
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Tommy B
authors.initials: TB
authors.lastname: Andersson
authors.forename: Ismael
authors.initials: I
authors.lastname: Zamora
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D065729:Cytochrome P-450 CYP2C9; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D012984:Software
chemical_list: D004791:Enzyme Inhibitors; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases