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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 Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval.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Methods: In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity.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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Ligand Binding to A2A receptor. Top panel: The top-docking pose of cisapride in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: A 2D-ligand interaction map for cisapride binding to the A2A receptor.
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Figure 7: Ligand Binding to A2A receptor. Top panel: The top-docking pose of cisapride in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: A 2D-ligand interaction map for cisapride binding to the A2A receptor.

Mentions: All of the derived cisapride analogues were docked to the A2A (PDB ID: 3QAK) active site using the approach described in the methods section. They were also docked to the pore domain of hERG1 model, and the cisapride derivative results were compared to the original cisapride docking scores. (FiguresĀ 6 and7, and Additional file1: Table S1) Four different molecular docking programs (AutoDock, Glide, FlexX, and GOLD) were used to study the binding interactions of cisapride and the cisapride derivatives in the A2A adenosine receptor and the hERG1 central cavity. Since the FlexX and AutoDock docking programs both underestimated the interaction energies of cisapride and its derivatives at both targets (i.e., hERG and A2A), GOLD and Glide/XP are generally preferred for the evaluation of binding affinities of known compounds. Our previously developed model of the trans-membrane domains, S1-S6, of open-state hERG1[1,26] was used to model the binding interactions of cisapride and its derivatives in the pore domain of the channel. Initially, cisapride was docked to A2A receptor as well as hERG1 model, and these binding scores were used as threshold values for all four docking programs. Cisapride derivatives that displayed similar/higher binding scores (absolute values) in the A2A receptor and lower binding scores in the hERG1 pore domain were considered for further analysis. For example, one of them (#11) labeled as Cisapride-D11 in the text had docking scores similar to original cisapride in the A2A binding pocket and considerably lower docking scores in the hERG PD, thus, it was considered for further rehabilitation.


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)

Ligand Binding to A2A receptor. Top panel: The top-docking pose of cisapride in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: A 2D-ligand interaction map for cisapride 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 7: Ligand Binding to A2A receptor. Top panel: The top-docking pose of cisapride in the human A2A adenosine receptor. (left) Binding interactions are zoomed and detailed (right). Bottom panel: A 2D-ligand interaction map for cisapride binding to the A2A receptor.
Mentions: All of the derived cisapride analogues were docked to the A2A (PDB ID: 3QAK) active site using the approach described in the methods section. They were also docked to the pore domain of hERG1 model, and the cisapride derivative results were compared to the original cisapride docking scores. (FiguresĀ 6 and7, and Additional file1: Table S1) Four different molecular docking programs (AutoDock, Glide, FlexX, and GOLD) were used to study the binding interactions of cisapride and the cisapride derivatives in the A2A adenosine receptor and the hERG1 central cavity. Since the FlexX and AutoDock docking programs both underestimated the interaction energies of cisapride and its derivatives at both targets (i.e., hERG and A2A), GOLD and Glide/XP are generally preferred for the evaluation of binding affinities of known compounds. Our previously developed model of the trans-membrane domains, S1-S6, of open-state hERG1[1,26] was used to model the binding interactions of cisapride and its derivatives in the pore domain of the channel. Initially, cisapride was docked to A2A receptor as well as hERG1 model, and these binding scores were used as threshold values for all four docking programs. Cisapride derivatives that displayed similar/higher binding scores (absolute values) in the A2A receptor and lower binding scores in the hERG1 pore domain were considered for further analysis. For example, one of them (#11) labeled as Cisapride-D11 in the text had docking scores similar to original cisapride in the A2A binding pocket and considerably lower docking scores in the hERG PD, thus, it was considered for further rehabilitation.

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