title: Kohonen maps for prediction of binding to human cytochrome P450 3A4.
abstract: The drug development process utilizes the parallel assessment of activity at a therapeutic target as well as absorption, distribution, metabolism, excretion, and toxicity properties of molecules. The development of novel, reliable, and inexpensive computational methods for the early assessment of metabolism and toxicity is becoming increasingly an important part of this process. We have used a computational approach for the assessment of drugs and drug-like compounds which bind to the cytochromes P450 (P450s) with experimentally determined Km values. The physicochemical properties of these compounds were calculated using molecular descriptor software and then analyzed using Kohonen self-organizing maps. This approach was applied to generate a P450-specific classification of nearly 500 drug compounds. We observed statistically significant differences in the molecular properties of low Km molecules for various P450s and suggest a relationship between 33 of these compounds and their CYP3A4-inhibitory activity. A test set of additional CYP3A4 inhibitors was used, and 13 of 15 of these molecules were colocated in the regions of low Km values. This computational approach represents a novel method for use in the generation of metabolism models, enabling the scoring of libraries of compounds for their Km values to numerous P450s.
authors.affiliation: Chemical Diversity Labs, Inc., San Diego, CA, USA.
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Balakin
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.forename: Andrey
authors.initials: A
authors.lastname: Bugrim
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.forename: Dmitry
authors.initials: D
authors.lastname: Korolev
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Nikolsky
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Skorenko
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Ivashchenko
authors.forename: Nikolay P
authors.initials: NP
authors.lastname: Savchuk
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikolskaya
mesh_terms: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D016208:Databases, Factual / Q000706:statistics & numerical data*; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D011485:Protein Binding / Q000502:physiology
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human