Identification of novel CYP2A6 inhibitors by virtual screening

Minna K Rahnasto; Hannu A Raunio; Carsten Wittekindt; Kaisa A Salminen; Jukka Leppänen; Risto O Juvonen; Antti Poso; Maija K Lahtela-Kakkonen

doi:10.1016/j.bmc.2011.09.054

Identification of novel CYP2A6 inhibitors by virtual screening

Bioorg Med Chem. 2011 Dec 1;19(23):7186-93. doi: 10.1016/j.bmc.2011.09.054. Epub 2011 Oct 4.

Authors

Minna K Rahnasto¹, Hannu A Raunio, Carsten Wittekindt, Kaisa A Salminen, Jukka Leppänen, Risto O Juvonen, Antti Poso, Maija K Lahtela-Kakkonen

Affiliation

¹ School of Pharmacy, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland. Minna.Rahnasto@uef.fi

PMID: 22019468
DOI: 10.1016/j.bmc.2011.09.054

Abstract

The human CYP2A6 enzyme metabolises several xenobiotics including nicotine, the addictive component in tobacco. Reduced activity of CYP2A6, either for genetic reasons or by administering inhibitors of CYP2A6, reduces tobacco smoking. The aim was to design novel inhibitors of CYP2A6 using 3D-QSAR analysis combined with virtual screening. A 3D-QSAR model was utilised to identify the most important features of the inhibitors, and this knowledge was used to design inhibitors for CYP2A6. Chemical database screening yielded several potent inhibitor candidates such as alkylamine derivatives (compound no. 5, IC(50)=0.1 μM) and 1-benzothiophene-3-carbaldehyde that can be used as lead compounds in the development of drugs for smoking reduction therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
Aryl Hydrocarbon Hydroxylases / chemistry*
Aryl Hydrocarbon Hydroxylases / metabolism
Cytochrome P-450 CYP2A6
Drug Evaluation, Preclinical / methods
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Humans
Kinetics
Models, Molecular
Quantitative Structure-Activity Relationship

Substances

Enzyme Inhibitors
Aryl Hydrocarbon Hydroxylases
CYP2A6 protein, human
Cytochrome P-450 CYP2A6