The hERG potassium channel is the molecular system responsible for conducting the cardiac IKr current , and the block of its activity by drugs can be associated with the risk of developing the drug-induced form of long QT syndrome. In this chapter, we review 2D and 3D quantitative structure-activity relationship (QSAR) models that, besides allowing one to predict the hERG liability of molecules, are also aimed at identifying physicochemical properties and other molecular features putatively responsible for the block of the channel by drugs. Also, we present results of classification procedures that are best suited to sort or classify compounds as active or inactive against hERG, but can also provide information on the molecular determinants of the effect. The main achievements of all these studies in terms of features characterizing the ability of binding to and blocking hERG are summarized. Some works that take into consideration docking models of drugs into the channel inner cavity are also illustrated and discussed in the light of their relevance toward ligand-based studies. Finally, open questions and perspectives on the use of these in silico approaches are briefly outlined.
QSAR and pharmacophores for drugs involved in hERG blockage
RECANATINI, MAURIZIO;CAVALLI, ANDREA
2008
Abstract
The hERG potassium channel is the molecular system responsible for conducting the cardiac IKr current , and the block of its activity by drugs can be associated with the risk of developing the drug-induced form of long QT syndrome. In this chapter, we review 2D and 3D quantitative structure-activity relationship (QSAR) models that, besides allowing one to predict the hERG liability of molecules, are also aimed at identifying physicochemical properties and other molecular features putatively responsible for the block of the channel by drugs. Also, we present results of classification procedures that are best suited to sort or classify compounds as active or inactive against hERG, but can also provide information on the molecular determinants of the effect. The main achievements of all these studies in terms of features characterizing the ability of binding to and blocking hERG are summarized. Some works that take into consideration docking models of drugs into the channel inner cavity are also illustrated and discussed in the light of their relevance toward ligand-based studies. Finally, open questions and perspectives on the use of these in silico approaches are briefly outlined.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.