The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation

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Abstract

In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (I _K1 and I _KACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking I _K1 and I _KACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC ₅₀ of I _K1 and I _KACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of I _K1 and I _KACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC ₅₀ of I _K1 block by chloroquine was similar to that of I _KACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of I _K1 and I _KACh can be a targeted therapeutic strategy for persistent atrial fibrillation.

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Most cited references 53

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Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.

John C Shelley, Anuradha Cholleti, Leah Frye … (2007)

Epik is a computer program for predicting pK(a) values for drug-like molecules. Epik can use this capability in combination with technology for tautomerization to adjust the protonation state of small drug-like molecules to automatically generate one or more of the most probable forms for use in further molecular modeling studies. Many medicinal chemicals can exchange protons with their environment, resulting in various ionization and tautomeric states, collectively known as protonation states. The protonation state of a drug can affect its solubility and membrane permeability. In modeling, the protonation state of a ligand will also affect which conformations are predicted for the molecule, as well as predictions for binding modes and ligand affinities based upon protein-ligand interactions. Despite the importance of the protonation state, many databases of candidate molecules used in drug development do not store reliable information on the most probable protonation states. Epik is sufficiently rapid and accurate to process large databases of drug-like molecules to provide this information. Several new technologies are employed. Extensions to the well-established Hammett and Taft approaches are used for pK(a) prediction, namely, mesomer standardization, charge cancellation, and charge spreading to make the predicted results reflect the nature of the molecule itself rather just for the particular Lewis structure used on input. In addition, a new iterative technology for generating, ranking and culling the generated protonation states is employed.

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Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field.

Devleena Shivakumar, Joshua Williams, YUJIE WU … (2010)

The accurate prediction of protein-ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small molecule provides a surrogate to the desolvation of the ligand in the thermodynamic process of protein-ligand binding. Here, we use explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation free energies of a set of 239 small molecules, spanning diverse chemical functional groups commonly found in drugs and drug-like molecules. We also compare the performance of absolute solvation free energies obtained using the OPLS_2005 force field with two other commonly used small molecule force fields-general AMBER force field (GAFF) with AM1-BCC charges and CHARMm-MSI with CHelpG charges. Using the OPLS_2005 force field, we obtain high correlation with experimental solvation free energies (R(2) = 0.94) and low average unsigned errors for a majority of the functional groups compared to AM1-BCC/GAFF or CHelpG/CHARMm-MSI. However, OPLS_2005 has errors of over 1.3 kcal/mol for certain classes of polar compounds. We show that predictions on these compound classes can be improved by using a semiempirical charge assignment method with an implicit bond charge correction.

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Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution.

Jeremy Greenwood, David R. Calkins, Arron Sullivan … (2010)

Generating the appropriate protonation states of drug-like molecules in solution is important for success in both ligand- and structure-based virtual screening. Screening collections of millions of compounds requires a method for determining tautomers and their energies that is sufficiently rapid, accurate, and comprehensive. To maximise enrichment, the lowest energy tautomers must be determined from heterogeneous input, without over-enumerating unfavourable states. While computationally expensive, the density functional theory (DFT) method M06-2X/aug-cc-pVTZ(-f) [PB-SCRF] provides accurate energies for enumerated model tautomeric systems. The empirical Hammett-Taft methodology can very rapidly extrapolate substituent effects from model systems to drug-like molecules via the relationship between pK(T) and pK(a). Combining the two complementary approaches transforms the tautomer problem from a scientific challenge to one of engineering scale-up, and avoids issues that arise due to the very limited number of measured pK(T) values, especially for the complicated heterocycles often favoured by medicinal chemists for their novelty and versatility. Several hundreds of pre-calculated tautomer energies and substituent pK(a) effects are tabulated in databases for use in structural adjustment by the program Epik, which treats tautomers as a subset of the larger problem of the protonation states in aqueous ensembles and their energy penalties. Accuracy and coverage is continually improved and expanded by parameterizing new systems of interest using DFT and experimental data. Recommendations are made for how to best incorporate tautomers in molecular design and virtual screening workflows.

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Author and article information

Contributors

Catalina Tobón: URI : https://loop.frontiersin.org/people/507066

Laura C. Palacio: URI : https://loop.frontiersin.org/people/814808

Bojjibabu Chidipi: URI : https://loop.frontiersin.org/people/811653

Diana P. Slough: URI : https://loop.frontiersin.org/people/812063

Nhi Tran: URI : https://loop.frontiersin.org/people/746455

Michelle Reiser: URI : https://loop.frontiersin.org/people/22836

Javier Saiz: URI : https://loop.frontiersin.org/people/40194

Journal

Journal ID (nlm-ta): Front Pharmacol

Journal ID (iso-abbrev): Front Pharmacol

Journal ID (publisher-id): Front. Pharmacol.

Title: Frontiers in Pharmacology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1663-9812

Publication date (Electronic): 27 November 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 1392

Affiliations

[1] ¹MATBIOM, Universidad de Medellín , Medellín, Colombia

[2] ²Molecular Pharmacology and Physiology Department, University of South Florida Morsani College of Medicine , Tampa, FL, United States

[3] ³Department of Chemistry, Tufts University , Medford, MA, United States

[4] ⁴Cardiology Department, University of South Florida Morsani College of Medicine , Tampa, FL, United States

[5] ⁵Ci2 B, Universitat Politècnica de València , Valencia, Spain

Author notes

Edited by: László Virág, University of Szeged, Hungary

Reviewed by: Lasse Skibsbye, Lundbeck, Denmark; Ursula Ravens, Dresden University of Technology, Germany

*Correspondence: Sami Noujaim, snoujaim@ 123456usf.edu

This article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology

†These authors have contributed equally to this work

Article

DOI: 10.3389/fphar.2019.01392

PMC ID: 6890839

PubMed ID: 31827438

SO-VID: 1d3ee876-2035-4e14-8cb1-f8fd58b68fe8

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 13 August 2019

Date accepted : 31 October 2019

Page count

Figures: 6, Tables: 0, Equations: 4, References: 72, Pages: 12, Words: 6366

Funding

Funded by: National Heart, Lung, and Blood Institute 10.13039/100000050

Funded by: Generalitat Valenciana 10.13039/501100003359

Funded by: American Heart Association 10.13039/100000968

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The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation

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Most cited references 53

Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.

Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field.

Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution.

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Cited by 8

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