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 Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval.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Methods: In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity.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

Show MeSH

Related in: MedlinePlus

The block-scheme for the work-flow in the computational rehabilitation of cisapride derivatives.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The block-scheme for the work-flow in the computational rehabilitation of cisapride derivatives.

Mentions: The workflow chart is shown in Figure 1. We combined step-by-step ligand modification focusing on key functional groups (Figure 2), two-target receptor docking, and molecular dynamics (MD) simulations to achieve this goal. First, we determined the key-molecular fragments of cisapride responsible for its high-affinity binding to the A2A receptor using all-atom MD simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding energy decompositions, which are similar to the approaches used in previous studies[11-13]. Next, small modifications of the sites responsible for the hERG blockade that played a less significant role in the stabilization of cisapride in the binding pocket of the A2A receptor were made. Our previously developed atomistic models of the open-state hERG1 channel were used to guide the modifications of cisapride. The most potent drug variants were tested for their binding to the central cavity of the hERG1 channel. The compounds that showed low affinities were then selected for further analysis. Because no crystal structure of the 5HT-4 receptor is currently available, we used a recently crystallized agonist-bound active GPCR from the same family as the target (the human adenosine A2A receptor, PDB ID: 3QAK)[14]. Since cisapride can selectively bind to a number of other GPCRs (including A2A receptor) with a similar range of binding affinity at a similar binding pocket, we chose to work with the available agonist-bound active target site of the A2A receptor to screen cisapride and its derivatives. Prior binding site[15] and comparative homology modeling studies for these receptors indicate a high similarity between the 5HT-4 and A2A binding pockets. Finally, a list of possible modifications to the original cisapride molecule was generated. MD simulations with MM/GB-SA computations, database drug screening and de novo design studies clearly showed that the shorter alkyl chain in cisapride analogues are key to retaining their binding to the A2A receptor while remediating the blockade of the hERG1 channel. To compare in silico results to de novo developments we screened a large panel of already synthesized cisapride analogs. Small molecule databanks (i.e., ZINC[16]) were screened for synthesized cisapride derivatives and the relevant literature was reviewed to identify their activity in both the GPCR and hERG targets. Dual target docking combined with all-atom MD simulations were used to establish the key interactions between cisapride and its derivatives responsible for their high-affinity binding to the A2A and how they receptor triggering hERG1 blockade. Using this combination of techniques it is possible to assess novel compounds a priori for their cardiotoxicity risks associated with hERG1 blockade as well as to identify sets of functional groups responsible for on-target binding.


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)

The block-scheme for the work-flow in the computational rehabilitation of cisapride derivatives.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: The block-scheme for the work-flow in the computational rehabilitation of cisapride derivatives.
Mentions: The workflow chart is shown in Figure 1. We combined step-by-step ligand modification focusing on key functional groups (Figure 2), two-target receptor docking, and molecular dynamics (MD) simulations to achieve this goal. First, we determined the key-molecular fragments of cisapride responsible for its high-affinity binding to the A2A receptor using all-atom MD simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding energy decompositions, which are similar to the approaches used in previous studies[11-13]. Next, small modifications of the sites responsible for the hERG blockade that played a less significant role in the stabilization of cisapride in the binding pocket of the A2A receptor were made. Our previously developed atomistic models of the open-state hERG1 channel were used to guide the modifications of cisapride. The most potent drug variants were tested for their binding to the central cavity of the hERG1 channel. The compounds that showed low affinities were then selected for further analysis. Because no crystal structure of the 5HT-4 receptor is currently available, we used a recently crystallized agonist-bound active GPCR from the same family as the target (the human adenosine A2A receptor, PDB ID: 3QAK)[14]. Since cisapride can selectively bind to a number of other GPCRs (including A2A receptor) with a similar range of binding affinity at a similar binding pocket, we chose to work with the available agonist-bound active target site of the A2A receptor to screen cisapride and its derivatives. Prior binding site[15] and comparative homology modeling studies for these receptors indicate a high similarity between the 5HT-4 and A2A binding pockets. Finally, a list of possible modifications to the original cisapride molecule was generated. MD simulations with MM/GB-SA computations, database drug screening and de novo design studies clearly showed that the shorter alkyl chain in cisapride analogues are key to retaining their binding to the A2A receptor while remediating the blockade of the hERG1 channel. To compare in silico results to de novo developments we screened a large panel of already synthesized cisapride analogs. Small molecule databanks (i.e., ZINC[16]) were screened for synthesized cisapride derivatives and the relevant literature was reviewed to identify their activity in both the GPCR and hERG targets. Dual target docking combined with all-atom MD simulations were used to establish the key interactions between cisapride and its derivatives responsible for their high-affinity binding to the A2A and how they receptor triggering hERG1 blockade. Using this combination of techniques it is possible to assess novel compounds a priori for their cardiotoxicity risks associated with hERG1 blockade as well as to identify sets of functional groups responsible for on-target binding.

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