Toward a Pharmacophore for Drugs Inducing the Long QT Syndrome:  Insights from a CoMFA Study of HERG K⁺ Channel Blockers

Abstract

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.

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

“…In this study, molecular weight (M W ), molecular fractional polar surface area (FPSA), and lipophilicity (ALogP) were used. We also calculated the pK a of the most positive basic nitrogen (pK a basic) based on previous pharmacophore models [7,14,15] . These four molecular properties were used as simple molecular descriptors for hERG blockage modeling and were calculated with the "Calculate Molecular Properties" protocol within Discovery Studio (version 3.0; Accelrys, San Diego, CA, USA) and components in Pipeline Pilot (version 7.5; Accelrys, San Diego, CA, USA).…”

“…In our study, we found that molecules with larger ALogP and M W but smaller FPSA are more likely to be blockers, which could be ascribed to the large pore size in hERG as well as the lipophilic character of the pore cavity [37] . Generally, a nitrogen positive ionizable center has been considered a common feature for many hERG blockers [7,50,51,52] . We calculated the pK a value of the most basic nitrogen of compounds (pK a _basic) and found that the pK a _basic of nonblocking molecules is likely to be zero.…”

“…In 2002, Cavalli et al used the CoMFA method analysis for 31 drugs and built a four-point pharmacophore model that included a positively charged tertiary amine flanked by three aromatic or hydrophobic centers, which was validated using 6 compounds (r 2 =0.744) [7] . In 2003, Keseru et al developed traditional and hologram QSAR (HQSAR) models with five descriptors, including ClogP, molar refractivity (CMR), partial negative surface area (PNSA1), polarizability (W2), and hydrophobicity (D3), to predict hERG affinities, for a test set of 13 compounds (r=0.75) [8] .…”

Physicochemical Features of the hERG Channel Drug Binding Site

“…Moreover, a description of the physicochemical features of the drug binding site would complement pharmacophore models (8,9) of drugs that block hERG channels and define the molecular basis for receptor fields predicted by these models. Toward this goal, we have used site-directed mutagenesis and voltage clamp analysis of mutant channels expressed in Xenopus oocytes to elucidate the molecular mechanisms of hERG channel block by structurally diverse drugs, including MK-499, cisapride, terfenadine, vesnarinone, chloroquine, and quinidine (10 -13).…”

“…Pharmacophore models predict that important features of potent hERG channel blockers are 1) a basic nitrogen that is usually protonated at physiological pH and 2) three hydrophobic centers of mass (centroids) arranged in a specific spatial pattern around the centrally located nitrogen (8,9). For many potent hERG blockers, these centroids are aromatic groups.…”