S2: High potency for hERG block

Minimal structural requirements for high potency for hERG block
Andrea Cavalli: Minimal structural requirements for high potency for hERG block

Andrea Cavalli


Dept. of Pharmacy and Biotechnology, University of Bologna
And Drug Discovery and Development, Unit Computation,
Italian Institute of Technology, Genova, Italy


Andrea Cavalli


1. Cavalli A. et al. J. Med. Chem. 2002, 45, 3844.
2. Masetti M. et al. J. Comput. Chem. 2008, 29, 795.
3. De Martino G.P. et al. J. Chem. Inf. Mod. 2013, 53, 159.
4. Ceccarini L. et al. PLoS ONE 2012, 7, 49017.
5. Cavalli A. et al. J. Med. Chem. 2012, 55, 4010.


Inhibition of the hERG potassium channel is responsible for remarkably dangerous cardiac side effects of drugs that can eventually lead to the so‐called drug-induced long-QT syndrome (LQTS). In certain conditions, LQTS can be lethal, and therefore the hERG binding liability of new chemical entities has greatly challenged several drug discovery programs.

Computational approaches to the prediction of hERG binding liability would greatly reduce costs of drug discovery, through early recognition of problem compounds, which potentially can bind the channel, being therefore responsible for lethal side effects. Since early this century, we have been working in the field of in silico hERG binding studies, using ligand- and structure-based approaches. In particular, as early as 2002, we published a study where we were able to build a 3D QSAR model and to identify the pharmacophoric functions responsible for hERG binding and inhibition.

(1) Subsequently, we turned our attention to structure-based approaches, which have however been remarkably hampered by the lack of an experimental structure of hERG. Homology modeling, molecular dynamics simulations, and flexible docking were therefore utilized to overcome this limitation, allowing us to provide a structure- based rationalization of the 3D QSAR model previously developed.

(2) More recently, we designed a strategy that explicitly took into account the conformations of the channel, their possible intrinsic symmetry, and the role played by the configurational entropy of ligands.

(3) Furthermore, from a biophysical standpoint, we recently investigated the K+ permeation through the channel via metadynamics simulations.

(4) Finally, based on the ligand- and structure-based models that had been generated over the years, we designed and discovered structurally simple compounds endowed with high hERG inhibition potency, pointing to what we named “minimal structural requirements for high potency for hERG block”.

(5) In this talk, I will be presenting the hERG issue and the major evolutions from a computational chemistry standpoint, with particular reference to the use of these approaches to the prediction of hERG binding and inhibition.