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Rehabilitating drug-induced long-QT promoters: in-silico design of hERG-neutral cisapride analogues with retained pharmacological activity.

Durdagi S, Randall T, Duff HJ, Chamberlin A, Noskov SY - BMC Pharmacol Toxicol (2014)

Bottom Line: A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach.This set was compared against a large dataset of commercially available cisapride analogs and derivatives.An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada. serdardurdagi@gmail.com.

ABSTRACT

Background: The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in the normal repolarization of the heart's action potential. Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have high potencies for their principal targets and are often irreplaceable, thus "rehabilitation" studies for decreasing their high hERG1 blocking affinities, while keeping them active at the binding sites of their targets, have been proposed to enable these drugs to re-enter the market.

Methods: In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity. Here we tested an a priori strategy to predict a compound's cardiotoxicity using de novo drug design with molecular docking and Molecular Dynamics (MD) simulations to generate a strategy for the rehabilitation of cisapride.

Results: We focused on two key receptors, a target interaction with the (adenosine) receptor and an off-target interaction with hERG1 channels. An analysis of the fragment interactions of cisapride at human A2A adenosine receptors and hERG1 central cavities helped us to identify the key chemical groups responsible for the drug activity and hERG1 blockade. A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach. This set was compared against a large dataset of commercially available cisapride analogs and derivatives.

Conclusions: An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1.

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Related in: MedlinePlus

Mosapride bidning to hERG1 pore domain. Top panel: The top-docking pose of mosapride that shows a low hERG PD blocking affinity in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: 2D-ligand interaction map for mosapride binding to the A2A receptor.
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Figure 8: Mosapride bidning to hERG1 pore domain. Top panel: The top-docking pose of mosapride that shows a low hERG PD blocking affinity in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: 2D-ligand interaction map for mosapride binding to the A2A receptor.

Mentions: Interestingly, ZINC20621758, also known commercially as mosapride, was detected via blinded dual-target screening to be a safer 5HT-4 agonist than cisapride. Potet et al.[6] showed that mosapride does not block the hERG channel, which is in agreement with lower binding scores predicted in silico. It is also a well-known agonist of the 5HT-4 receptor. The IC50 of mosapride binding to the hERG channel is ~16.5 μM. Mosapride carries a significant decrease of cardiovascular risks related to alterations in QT intervals according to preclinical studies[42,39,43]. Carlsson et al. used a rabbit model of the acquired long QT syndrome, and while cisapride prolonged the QT interval, mosapride did not[39,44,45]. One of the key differences between mosapride and cisapride is a shorter linker between aromatic rings that, as predicted in the dual-target de novo drug modeling, will have an immediate effect on the drug-hERG PD interactions. Figure 8 shows the top Induced Fit docking pose of mosapride in the A2A receptor. Cisapride and mosapride have different binding modes in the A2A receptor due to a different number of CH2 groups in the linker. Additional file1: Figure S2 shows a superposition of the top-docking poses of cisapride and mosapride.


Rehabilitating drug-induced long-QT promoters: in-silico design of hERG-neutral cisapride analogues with retained pharmacological activity.

Durdagi S, Randall T, Duff HJ, Chamberlin A, Noskov SY - BMC Pharmacol Toxicol (2014)

Mosapride bidning to hERG1 pore domain. Top panel: The top-docking pose of mosapride that shows a low hERG PD blocking affinity in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: 2D-ligand interaction map for mosapride binding to the A2A receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016140&req=5

Figure 8: Mosapride bidning to hERG1 pore domain. Top panel: The top-docking pose of mosapride that shows a low hERG PD blocking affinity in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: 2D-ligand interaction map for mosapride binding to the A2A receptor.
Mentions: Interestingly, ZINC20621758, also known commercially as mosapride, was detected via blinded dual-target screening to be a safer 5HT-4 agonist than cisapride. Potet et al.[6] showed that mosapride does not block the hERG channel, which is in agreement with lower binding scores predicted in silico. It is also a well-known agonist of the 5HT-4 receptor. The IC50 of mosapride binding to the hERG channel is ~16.5 μM. Mosapride carries a significant decrease of cardiovascular risks related to alterations in QT intervals according to preclinical studies[42,39,43]. Carlsson et al. used a rabbit model of the acquired long QT syndrome, and while cisapride prolonged the QT interval, mosapride did not[39,44,45]. One of the key differences between mosapride and cisapride is a shorter linker between aromatic rings that, as predicted in the dual-target de novo drug modeling, will have an immediate effect on the drug-hERG PD interactions. Figure 8 shows the top Induced Fit docking pose of mosapride in the A2A receptor. Cisapride and mosapride have different binding modes in the A2A receptor due to a different number of CH2 groups in the linker. Additional file1: Figure S2 shows a superposition of the top-docking poses of cisapride and mosapride.

Bottom Line: A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach.This set was compared against a large dataset of commercially available cisapride analogs and derivatives.An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada. serdardurdagi@gmail.com.

ABSTRACT

Background: The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in the normal repolarization of the heart's action potential. Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have high potencies for their principal targets and are often irreplaceable, thus "rehabilitation" studies for decreasing their high hERG1 blocking affinities, while keeping them active at the binding sites of their targets, have been proposed to enable these drugs to re-enter the market.

Methods: In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity. Here we tested an a priori strategy to predict a compound's cardiotoxicity using de novo drug design with molecular docking and Molecular Dynamics (MD) simulations to generate a strategy for the rehabilitation of cisapride.

Results: We focused on two key receptors, a target interaction with the (adenosine) receptor and an off-target interaction with hERG1 channels. An analysis of the fragment interactions of cisapride at human A2A adenosine receptors and hERG1 central cavities helped us to identify the key chemical groups responsible for the drug activity and hERG1 blockade. A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach. This set was compared against a large dataset of commercially available cisapride analogs and derivatives.

Conclusions: An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1.

Show MeSH
Related in: MedlinePlus