Identification of novel CYP2A6 inhibitors by virtual screening.
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.
School of Pharmacy, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland. Minna.Rahnasto@uef.fi
Minna K
MK
Rahnasto
Hannu A
HA
Raunio
Carsten
C
Wittekindt
Kaisa A
KA
Salminen
Jukka
J
Leppänen
Risto O
RO
Juvonen
Antti
A
Poso
Maija K
MK
Lahtela-Kakkonen
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6