The pharmacophore hypotheses of I(Kr) potassium channel blockers: novel class III antiarrhythmic agents.
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
Du
Lü-Pei
LP
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
Tsai
Keng-Chang
KC
Li
Min-Yong
MY
You
Qi-Dong
QD
Xia
Lin
L
D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification; D008954:Models, Biological; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry*; D015221:Potassium Channels / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods
D000889:Anti-Arrhythmia Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels