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Vol. 301, Issue 2, 427-434, May 2002

Three-Dimensional Quantitative Structure-Activity Relationship for Inhibition of Human Ether-a-Go-Go-Related Gene Potassium Channel

Sean Ekins1 , William J. Crumb, R. Dustan Sarazan, James H. Wikel and Steven A. Wrighton

Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana (S.E., R.D.S., J.H.W., S.A.W.); and Department of Pediatrics, Division of Cardiology, Tulane University School of Medicine, New Orleans, Louisiana (W.J.C.)

The protein product of the human ether-a-go-go gene (hERG) is a potassium channel that when inhibited by some drugs may lead to cardiac arrhythmia. Previously, a three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore model was constructed using Catalyst with in vitro inhibition data for antipsychotic agents. The rationale of the current study was to use a combination of in vitro and in silico technologies to further test the pharmacophore model and qualitatively predict whether molecules are likely to inhibit this potassium channel. These predictions were assessed with the experimental data using the Spearman's rho rank correlation. The antipsychotic-based hERG inhibitor model produced a statistically significant Spearman's rho of 0.71 for 11 molecules. In addition, 15 molecules from the literature were used as a further test set and were also well ranked by the same model with a statistically significant Spearman's rho value of 0.76. A Catalyst General hERG pharmacophore model was generated with these literature molecules, which contained four hydrophobic features and one positive ionizable feature. Linear regression of log-transformed observed versus predicted IC50 values for this training set resulted in an r2 value of 0.90. The model based on literature data was evaluated with the in vitro data generated for the original 22 molecules (including the antipsychotics) and illustrated a significant Spearman's rho of 0.77. Thus, the Catalyst 3D-QSAR approach provides useful qualitative predictions for test set molecules. The model based on literature data therefore provides a potentially valuable tool for discovery chemistry as future molecules may be synthesized that are less likely to inhibit hERG based on information provided by a pharmacophore for the inhibition of this potassium channel.

1 Present address: Concurrent Pharmaceuticals, Inc., One Broadway, 14th Floor, Cambridge, MA 02142.

0022-3565/02/3012-0427$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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