The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents

  • Bioorg Med Chem Lett. 2004 Sep 20;14(18):4771-7. doi: 10.1016/j.bmcl.2004.06.070.
Lü-Pei Du  1 ,  Keng-Chang Tsai ,  Min-Yong Li ,  Qi-Dong You ,  Lin Xia
Affiliations
  • 1. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
PMID: 15324906 DOI: 10.1016/j.bmcl.2004.06.070
Abstract

Predictive pharmacophore models were developed for a large series of I(Kr) Potassium Channel blockers as class III antiarrhythmic agents using HypoGen in Catalyst software. The pharmacophore hypotheses were generated using a training set consisting of 34 compounds carefully selected from documents. Their biological data, expressed as IC(50), spanned from 1.5 nM to 2.8 mM with 7 orders difference. The most predictive hypothesis (Hypo1), consisting of four features (one positive ionizable feature, two aromatic rings and one hydrophobic group), had a best correlation coefficient of 0.825, a lowest rms deviation of 1.612, and a highest cost difference (null cost-total cost) of 77.552, which represents a true correlation and a good predictivity. The hypothesis Hypo1 was then validated by a test set consisting of 21 compounds and by a cross-validation of 95% confidence level with randomizing the data using CatScramble program. Accordingly, our model has strong predictivity to identify structural diverse I(Kr) Potassium Channel blockers with desired biological activity by virtual screening

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