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A Ligand-Based Virtual Screening Approach to Identify Small Molecules as hERG Channel Activators

[ Vol. 18 , Issue. 3 ]

Author(s):

Elisa Giacomini, Rosa Buonfiglio, Matteo Masetti, Yuhong Wang, Gea-Ny Tseng, Marinella Roberti and Maurizio Recanatini   Pages 269 - 280 ( 12 )

Abstract:


The hERG potassium channel is currently emerging as a potential target for the treatment of some forms of arrhythmias or to contrast an unintentional channel block caused by drugs. Despite its therapeutic relevance, so far only few compounds are described as able to enhance channel function by potentiating hERG currents. This gap is also related to the lack of hERG crystal structure which strongly limits the possibility to employ structure-based techniques in the search and design of novel activators. To overcome this limitation, in the present work, a ligand-based virtual screening was performed using as separate search queries two conformations of NS1643, the most deeply investigated and better characterized hERG activator. The library of compounds resulting from the virtual screening was then clustered based on recurring chemical features, and 5 hits were selected to be evaluated for their ability to enhance hERG current in vitro. Compound 3 showed a good activating effect, also displaying a mechanism of action similar to that of NS1643. Moreover, the most interesting compounds were further investigated by synthesizing in a parallel fashion some analogs, with the aim to get insights about structure-activity relationships.

Keywords:

Activators, electrophysiology, hERG potassium channel, ligand-based virtual screening, NS1643, parallel synthesis.

Affiliation:

Department of Pharmacy and Biotechnology, Alma Mater Studiorum - Universita di Bologna, via Belmeloro 6, 40126 Bologna, Italy.



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