Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.
In this paper, we present a pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers. The blockade of HERG K(+) channels is one of the most important molecular mechanisms through which QT-prolonging drugs increase cardiac action potential duration. Since QT prolongation is one of the most undesirable side effects of drugs, we first tried to identify the minimum set of molecular features responsible for this action and then we attempted to develop a quantitative model correlating the 3D stereoelectronic characteristics of the molecules with their HERG blocking potency. Having considered an initial set of 31 QT-prolonging drugs for which the HERG K(+) channel blocking activity was measured on mammalian transfected cells, we started the construction of a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. This in silico tool might be useful in the design of new drug candidates devoid of the physicochemical features likely to cause the above-mentioned side effect.
Cavalli
Andrea
A
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.
Poluzzi
Elisabetta
E
De Ponti
Fabrizio
F
Recanatini
Maurizio
M
D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000737:chemistry*; D027682:Cation Transport Proteins; D016000:Cluster Analysis; D016208:Databases, Factual; D051638:Ether-A-Go-Go Potassium Channels; D008133:Long QT Syndrome / Q000139:chemically induced*; D008958:Models, Molecular; D008968:Molecular Conformation; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000737:chemistry*; D024642:Potassium Channels, Voltage-Gated; D021281:Quantitative Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated