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Predictive three-dimensional quantitative structure-activity relationship of cytochrome P450 1A2 inhibitors.

Journal of medicinal chemistry (2005-05-27)
Laura E Korhonen, Minna Rahnasto, Niina J Mähönen, Carsten Wittekindt, Antti Poso, Risto O Juvonen, Hannu Raunio
ABSTRACT

The purpose of this study was to determine the cytochrome P450 1A2 (CYP1A2) inhibition potencies of structurally diverse compounds to create a comprehensive three-dimensional quantitative structure-activity relationship (3D-QSAR) model of CYP1A2 inhibitors and to use this model to predict the inhibition potencies of an external set of compounds. Fifty-two compounds including naphthalene, lactone and quinoline derivatives were assayed in a 96-well plate format for CYP1A2 inhibition activity using 7-ethoxyresorufin O-dealkylation as the probe reaction. The IC50 values of the tested compounds varied from 2.3 microM to over 40,000 microM. On the basis of this data set, a comparative molecular field analysis (CoMFA) and GRID/GOLPE models were created that yielded novel structural information about the interaction between inhibitory molecules and the CYP1A2 active site. The created CoMFA model was able to accurately predict inhibitory potencies of several structurally unrelated compounds, including selective inhibitors of other cytochrome P450 forms.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
p-Anisaldehyde, 98%
Sigma-Aldrich
Naphthalene, 99%
Sigma-Aldrich
(−)-Nicotine, ≥99% (GC), liquid
Sigma-Aldrich
1-Naphthol, ReagentPlus®, ≥99%
Sigma-Aldrich
2-Naphthol, 99%
Sigma-Aldrich
Biphenyl, ReagentPlus®, 99.5%
Supelco
Naphthalene, analytical standard
Sigma-Aldrich
Biphenyl, ≥99%
Sigma-Aldrich
1-Methylnaphthalene, 95%
Supelco
(−)-Nicotine, PESTANAL®, analytical standard
Sigma-Aldrich
1-Chloronaphthalene, technical grade
Supelco
Melting point standard 79-81°C, analytical standard
Sigma-Aldrich
2-Methylnaphthalene (β), 97%
Sigma-Aldrich
γ-Valerolactone, ≥99%, FCC, FG
Supelco
p-Anisaldehyde, analytical standard
Sigma-Aldrich
2-Methoxynaphthalene, 99%
Sigma-Aldrich
Naphthalene, suitable for scintillation, ≥99%
Supelco
(−)-Nicotine solution, 1.0 mg/mL, analytical standard, for drug analysis
Sigma-Aldrich
(−)-Cotinine, ≥98%
Sigma-Aldrich
Butylbenzene, ≥99%
Sigma-Aldrich
γ-Decalactone, ≥98%, FG, FCC
Sigma-Aldrich
Indan, 95%
Supelco
Biphenyl, PESTANAL®, analytical standard
Sigma-Aldrich
γ-Dodecalactone, ≥97%, FCC, FG
Sigma-Aldrich
γ-Undecalactone, ≥98%, FCC, FG
Sigma-Aldrich
1,4-Dimethylnaphthalene, 95%
Sigma-Aldrich
p-Anisaldehyde, ≥97.5%, FCC, FG
Sigma-Aldrich
1-Naphthol, puriss. p.a., reag. Ph. Eur., ≥99% (GC)
Sigma-Aldrich
Anisaldehyde solution
Supelco
2-Methylnaphthalene, analytical standard