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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 Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval.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Methods: In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity.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

(left) The dynamics of cisapride in the A2A binding pocket (Backbone RMSD after 50 ns ~3.1 Å). (right) Summary of the MM/GB-SA decomposition analysis (per-residue and per-group contributions) from the last 40 ns of the MD simulation of the A2A-cisapride complex.
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Figure 4: (left) The dynamics of cisapride in the A2A binding pocket (Backbone RMSD after 50 ns ~3.1 Å). (right) Summary of the MM/GB-SA decomposition analysis (per-residue and per-group contributions) from the last 40 ns of the MD simulation of the A2A-cisapride complex.

Mentions: As stated in the Introduction, one of the major goals of this study was to identify the determinants of the cisapride blockade of hERG and its binding to the A2A receptor which serves as a suitable model for the 5HT-4 receptor. Although our docking studies unambiguously identified binding pockets in both proteins, the orientation of the bound ligand was less well defined. To account for the limited resolution of our docking studies, we ran five independent 50 ns full-membrane all-atom molecular dynamics (MD) simulations using the top 5 poses from docking analysis as a starting point. All simulations were found to produce stable trajectories with membrane proteins displaying heavy atom RMSD values of ~3 to 4 Å, which is comparable to root mean squared fluctuation (RMSF) estimates from previous studies of K-channels with available crystal structures[33]. The averaged locations of the ligand after MD simulations are shown in Figures 3 and4. Cisapride bound in either membrane protein (A2A receptor or hERG1 open-state channel model) displays significant conformational dynamics in the binding site with an average RMSD value of ~1.1 Å relative to the average structure. The backbone RMSD of the hERG tetramer channel after 50 ns was approximately 5.3 Å including deviations from the symmetric tetramer; the corresponding values for the monomers were from 3.5 to 4.2 Å. The positional fluctuations in backbone atoms of residues forming the pore domain (PD) of the hERG1 monomer plateaued at a RMSD of ~2.4-2.9 Å. These values are similar to those reported previously for MD simulations of Kv channels[32]. The backbone RMSDs of the A2A receptor plateaued at ~3.1 Å. The considerable dynamics of the receptor and the bound ligand suggest that explicitly accounting for site and ligand flexibility in evaluation of the binding energies is necessary. To circumvent obvious limitations of the chosen docking strategy and to identify key interacting partners e.g. relevant amino-acid residues and key functional groups in the drug, we performed MM/GBSA computations to estimate the binding affinity of cisapride in the A2A receptor and the open-state hERG1 model. The distribution of binding enthalpies from 5 independent simulations is shown in the Figure 5. The average binding enthalpies for cisapride to the hERG1 and A2A are –21.3 ± 2.8 kcal/mol and -24.3 ± 1.9 kcal/mol, respectively.


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)

(left) The dynamics of cisapride in the A2A binding pocket (Backbone RMSD after 50 ns ~3.1 Å). (right) Summary of the MM/GB-SA decomposition analysis (per-residue and per-group contributions) from the last 40 ns of the MD simulation of the A2A-cisapride complex.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: (left) The dynamics of cisapride in the A2A binding pocket (Backbone RMSD after 50 ns ~3.1 Å). (right) Summary of the MM/GB-SA decomposition analysis (per-residue and per-group contributions) from the last 40 ns of the MD simulation of the A2A-cisapride complex.
Mentions: As stated in the Introduction, one of the major goals of this study was to identify the determinants of the cisapride blockade of hERG and its binding to the A2A receptor which serves as a suitable model for the 5HT-4 receptor. Although our docking studies unambiguously identified binding pockets in both proteins, the orientation of the bound ligand was less well defined. To account for the limited resolution of our docking studies, we ran five independent 50 ns full-membrane all-atom molecular dynamics (MD) simulations using the top 5 poses from docking analysis as a starting point. All simulations were found to produce stable trajectories with membrane proteins displaying heavy atom RMSD values of ~3 to 4 Å, which is comparable to root mean squared fluctuation (RMSF) estimates from previous studies of K-channels with available crystal structures[33]. The averaged locations of the ligand after MD simulations are shown in Figures 3 and4. Cisapride bound in either membrane protein (A2A receptor or hERG1 open-state channel model) displays significant conformational dynamics in the binding site with an average RMSD value of ~1.1 Å relative to the average structure. The backbone RMSD of the hERG tetramer channel after 50 ns was approximately 5.3 Å including deviations from the symmetric tetramer; the corresponding values for the monomers were from 3.5 to 4.2 Å. The positional fluctuations in backbone atoms of residues forming the pore domain (PD) of the hERG1 monomer plateaued at a RMSD of ~2.4-2.9 Å. These values are similar to those reported previously for MD simulations of Kv channels[32]. The backbone RMSDs of the A2A receptor plateaued at ~3.1 Å. The considerable dynamics of the receptor and the bound ligand suggest that explicitly accounting for site and ligand flexibility in evaluation of the binding energies is necessary. To circumvent obvious limitations of the chosen docking strategy and to identify key interacting partners e.g. relevant amino-acid residues and key functional groups in the drug, we performed MM/GBSA computations to estimate the binding affinity of cisapride in the A2A receptor and the open-state hERG1 model. The distribution of binding enthalpies from 5 independent simulations is shown in the Figure 5. The average binding enthalpies for cisapride to the hERG1 and A2A are –21.3 ± 2.8 kcal/mol and -24.3 ± 1.9 kcal/mol, respectively.

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