title: Classification models for CYP450 3A4 inhibitors and non-inhibitors.
abstract: Cytochrome P450 3A4 (CYP3A4) is the predominant enzyme involved in the oxidative metabolic pathways of many drugs. The inhibition of this enzyme in many cases leads to an undesired accumulation of the administered therapeutic agent. The purpose of this study is to develop in silico model that can effectively distinguish human CYP3A4 inhibitors from non-inhibitors. Structural diversity of the drug-like compounds CYP3A4 inhibitors and non-inhibitors was obtained from Fujitsu Database and Korea Research Institute of Chemical Technology (KRICT) as training and test sets, respectively. Recursive Partitioning (RP) method was introduced for the classification of inhibitor and non-inhibitor of CYP3A4 because it is an easy and quick classification method to implement. The 2D molecular descriptors were used to classify the compounds into respective inhibitors and non-inhibitors by calculation of the physicochemical properties of CYP3A4 inhibitors such as molecular weights and fractions of 2D VSA chargeable groups. The RP tree model reached 72.33% of accuracy and exceeded this percentage for the sensitivity (75.82%) parameter. This model is further validated by the test set where both accuracy and sensitivity were 72.58% and 82.64%, respectively. The accuracy of the random forest model was increased to 73.8%. The 2D descriptors sufficiently represented the molecular features of CYP3A4 inhibitors. Our model can be used for the prediction of either CYP3A4 inhibitors or non-inhibitors in the early stages of the drug discovery process.
authors.affiliation: Institute of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Choi
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Hanjo
authors.initials: H
authors.lastname: Kim
authors.forename: Nam Sook
authors.initials: NS
authors.lastname: Kang
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
authors.forename: Seung-Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Jihoon
authors.initials: J
authors.lastname: Jung
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008970:Molecular Weight; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human