QSAR models of cytochrome P450 enzyme 1A2 inhibitors using CoMFA, CoMSIA and HQSAR

Abstract

Quantitative structure–activity relationship (QSAR) studies were conducted on an in-house database of cytochrome P450 enzyme 1A2 inhibitors using the comparative molecular field analysis (CoMFA), comparative molecular similarity analysis (CoMSIA) and hologram QSAR (HQSAR) approaches. The database consisted of 36 active molecules featuring varied core structures. The model based on the naphthalene substructure alignment incorporating 19 molecules yielded the best model with a CoMFA cross validation value q² of 0.667 and a Pearson correlation coefficient r² of 0.976; a CoMSIA q² value of 0.616 and r² value of 0.985; and a HQSAR q² value of 0.652 and r² value of 0.917. A second model incorporating 34 molecules aligned using the benzene substructure yielded an acceptable CoMFA model with q² value of 0.5 and r² value of 0.991. Depending on the core structure of the molecule under consideration, new CYP1A2 inhibitors will be designed based on the results from these models.

Keywords:

• molecular operating environment
• molecular orbital package
• comparative molecular field analysis
• comparative molecular similarity analysis
• hologram QSAR
• partial least squares

Acknowledgments

We would like to thank the NIH and Louisiana Cancer Research Consortium for financially supporting this work through the grants NIH SC1 GMO84722 and NIH RCMI 1G12RR026260.