A 3D-QSAR model for CYP2D6 inhibition in the aryloxypropanolamine series

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 17; pp. 3816 - 3820
• Main Authors: Vaz, Roy J., Nayeem, Akbar, Santone, Kenneth, Chandrasena, Gamini, Gavai, Ashvinikumar V.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2005; Elsevier
• Subjects: 3D-QSAR; Animals; Aryloxypropanolamines; Biological and medical sciences; CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Humans; Inhibitory Concentration 50; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Propanolamines - chemistry; Propanolamines - pharmacology; Quantitative Structure-Activity Relationship; Substrate Specificity; 3D-QSAR; Aryloxypropanolamines; CYP2D6; Isozyme; Homology; Modeling; Comparative molecular similarity indices analysis method; Hydroxyether; Structure activity relation; Molecular model; Inhibition; Unspecific monooxygenase; Aminoalcohol; Enzyme; Cytochrome P450; Prediction; Vertebrata; Three dimensional model; Mammalia; Synthetic product; Affinity; Drug-metabolizing enzyme; Oxidoreductases; Conformation; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.06.007

A comparative molecular similarity index analysis (CoMSiA) has been performed for cytochrome P450 2D6 inhibition on a series of aryloxypropanolamines to determine the factors contributing to this activity. The model is in agreement with a CYP2D6 homology model constructed on the basis of the mammalian CYP2C5 crystal structure. The energy minimized conformations were generated using the systematic search methodology in Sybyl 6.7. The model not only elucidated the relationship between structure and biological activity but, more importantly, provided useful strategies to modulate CYP2D6 affinity in the aryloxypropanolamine series.