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

BMC Clinical Pharmacology

Sergei Y Noskov¹  Adam Chamberlin³  Henry J Duff²  Trevor Randall³  Serdar Durdagi⁴ 

[1] Center for Molecular Simulations, Department of Biological Sciences, BI-447, University of Calgary, 2500 University Drive, NW, Calgary T3A2T3, Canada;Libin Cardiovascular Institute of Alberta, Department of Cardiac Sciences, University of Calgary, Calgary, Canada;Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada;Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey

关键词: Drug databases;    Drug design;    Molecular dynamics simulations;    Molecular docking;    5HT-4 receptor;    A_2A adenosine receptor;    hERG K channel;   

Others  :  1228656
DOI  :  10.1186/2050-6511-15-14

 received in 2013-10-18, accepted in 2014-02-24,  发布年份 2014

【 摘 要 】

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, I_Kr, 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 Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval.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In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity.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 A_2A 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.

【 授权许可】

   
2014 Durdagi et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】

• [1]Durdagi S, Deshpande S, Duff HJ, Noskov SY: Modeling of open, closed, and open-inactivated states of the hERG1 channel: structural mechanisms of the state-dependent drug binding. J Chem Inf Model 2012, 52(10):2760-2774.
• [2]Durdagi S, Duff HJ, Noskov SY: Combined receptor and ligand-based approach to the universal pharmacophore model development for studies of drug blockade to the hERG1 pore domain. J Chem Inf Model 2011, 51(2):463-474.
• [3]Durdagi S, Subbotina J, Lees-Miller J, Guo J, Duff HJ, Noskov SY: Insights into the molecular mechanism of hERG1 channel activation and blockade by drugs. Curr Med Chem 2010, 17(30):3514-3532.
• [4]Shieh CC, Coghlan M, Sullivan JP, Gopalakrishnan M: Potassium channels: Molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 2000, 52(4):557-593.
• [5]Ashcroft FM: Ion Channels and Disease: Channelopathies. San Diego: Academic Press; 2000.
• [6]Potet F, Bouyssou T, Escande D, Baro I: Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-a-gogo K + channel. J Pharmacol Exp Ther 2001, 299(3):1007-1012.
• [7]Mohammad S, Zhou ZF, Gong QM, January CT: Blockage of the HERG human cardiac K + channel by the gastrointestinal prokinetic agent cisapride. Am J Physiol-Heart C 1997, 273(5):H2534-H2538.
• [8]Rampe D, Roy ML, Dennis A, Brown AM: A mechanism for the proarrhythmic effects of cisapride (Propulsid): high affinity blockade of the human cardiac potassium channel HERG. Febs Lett 1997, 417(1):28-32.
• [9]Walker BD, Singleton CB, Bursill JA, Wyse KR, Valenzuela SM, Qiu MR, Breit SN, Campbell TJ: Inhibition of the human ether-a-go-go-related gene (HERG) potassium channel by cisapride: affinity for open and inactivated states. Brit J Pharmacol 1999, 128(2):444-450.
• [10]Drolet B, Khalifa M, Daleau P, Hamelin BA, Turgeon J: Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval. Circulation 1998, 97(2):204-210.
• [11]Swanson JMJ, Henchman RH, McCammon JA: Revisiting free energy calculations: a theoretical connection to MM/PBSA and direct calculation of the association free energy. Biophys J 2004, 86(1):67-74.
• [12]Noskov SY, Lim C: Free energy decomposition of protein-protein interactions. Biophys J 2001, 81(2):737-750.
• [13]Wright JD, Noskov SY, Lim C: Factors governing loss and rescue of DNA binding upon single and double mutations in the p53 core domain. Nucleic Acids Res 2002, 30(7):1563-1574.
• [14]Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC: Structure of an agonist-bound human A2A adenosine receptor. Science 2011, 332(6027):322-327.
• [15]Mialet J, Dahmoune Y, Lezoualc’h F, Berque-Bestel I, Eftekhari P, Hoebeke J, Sicsic S, Langlois M, Fischmeister R: Exploration of the ligand binding site of the human 5-HT4 receptor by site-directed mutagenesis and molecular modeling. Brit J Pharmacol 2000, 130(3):527-538.
• [16]Irwin JJ, Sterling T, Musinger MM, Bolstad ES, Coleman RG: ZINC: a free tool to discover chemistry for biology. J Chem Inf Model 2012, 52:1757-1768.
• [17]Software Package: Schrödinger Release 2014-1: Maestro, version 9.7. New York, NY: Schrödinger, LLC; 2014.
• [18]Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT: Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006, 49(21):6177-6196.
• [19]Bohm HJ: The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des 1994, 8(3):243-256.
• [20]Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ: AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 2009, 30(16):2785-2791.
• [21]Jones G, Willett P, Glen RC, Leach AR, Taylor R: Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997, 267(3):727-748.
• [22]Kopp J, Schwede T: The SWISS-MODEL Repository of annotated three-dimensional protein structure homology models. Nucleic Acids Res 2004, 32:D230-D234.
• [23]Thompson JD, Higgins DG, Gibson TJ: Clustal-W - improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific Gap penalties and weight matrix choice. Nucleic Acids Res 1994, 22(22):4673-4680.
• [24]Benkert P, Biasini M, Schwede T: Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 2011, 27(3):343-350.
• [25]Brooks BR, Brooks CL 3rd, Mackerell AD Jr, Nilsson L, Petrella RJ, Roux B, Won Y, Archontis G, Bartels C, Boresch S, Caflisch A, Caves L, Cui Q, Dinner AR, Feig M, Fischer S, Gao J, Hodoscek M, Im W, Kuczera K, Lazaridis T, Ma J, Ovchinnikov V, Paci E, Pastor RW, Post CB, Pu JZ, Schaefer M, Tidor B, Venable RM, et al.: CHARMM: the biomolecular simulation program. J Comput Chem 2009, 30(10):1545-1614.
• [26]Subbotina J, Yarov-Yarovoy V, Lees-Miller J, Durdagi S, Guo JQ, Duff HJ, Noskov SY: Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations. Proteins 2010, 78(14):2922-2934.
• [27]Jo S, Lim JB, Klauda JB, Im W: CHARMM-GUI membrane builder for mixed bilayers and its application to yeast membranes. Biophys J 2009, 97(1):50-58.
• [28]Dominy BN, Brooks CL: Development of a generalized born model parametrization for proteins and nucleic acids. J Phys Chem B 1999, 103(18):3765-3773.
• [29]Dominy BN, Brooks CL: Methodology for protein-ligand binding studies: Application to a model for drug resistance, the HIV/FIV protease system. Proteins-Structure Function and Genetics 1999, 36(3):318-331.
• [30]Nina M, Beglov D, Roux B: Atomic radii for continuum electrostatics calculations based on molecular dynamics free energy simulations. J Phys Chem B 1997, 101(26):5239-5248.
• [31]Chanda B, Asamoah OK, Blunck R, Roux B, Bezanilla F: Gating charge displacement in voltage-gated ion channels involves limited transmembrane movement. Nature 2005, 436(7052):852-856.
• [32]Im W, Feig M, Brooks CL: An implicit membrane generalized born theory for the study of structure, stability, and interactions of membrane proteins. Biophys J 2003, 85(5):2900-2918.
• [33]Noskov SY, Berneche S, Roux B: Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands. Nature 2004, 431(7010):830-834.
• [34]Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP: hERG K+ chanels: Structure, Function and Clinical Significance. Physiol Rev 2012, 92(3):1393-1478.
• [35]Ng CA, Torres AM, Pages G, Kuchel PW, Vandenberg JI: Insights into hERG K + channel structure and function from NMR studies. Eur Biophys J Biophy 2013, 42(1):71-79.
• [36]Perry M, Sanguinetti M, Mitcheson J: Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol-London 2010, 588(17):3157-3167.
• [37]Perry M, de Groot MJ, Helliwell R, Leishman D, Tristani-Firouzi M, Sanguinetti MC, Mitcheson J: Structural determinants of HERG channel block by clofilium and ibutilide. Mol Pharmacol 2004, 66(2):240-249.
• [38]Lees-Miller JP, Subbotina JO, Guo JQ, Yarov-Yarovoy V, Noskov SY, Duff HJ: Interactions of H562 in the S5 Helix with T618 and S621 in the Pore Helix Are Important Determinants of hERG1 Potassium Channel Structure and Function. Biophys J 2009, 96(9):3600-3610.
• [39]Carlsson L, Amos GJ, Andersson B, Drews L, Duker G, Wadstedt G: Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: Implications for proarrhythmic potential? J Pharmacol Exp Ther 1997, 282(1):220-227.
• [40]Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, Mackerell AD Jr: CHARMM General Force Field: A Force Field for Drug-Like Molecules Compatible with the CHARMM All-Atom Additive Biological Force Fields. J Comput Chem 2010, 31(4):671-690.
• [41]Chen J, Seebohm G, Sanguinetti MC: Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. P Natl Acad Sci USA 2002, 99(19):12461-12466.
• [42]Kii Y, Ito T: Effects of 5-HT4-receptor agonists, cisapride, mosapride citrate, and zacopride, on cardiac action potentials in guinea pig isolated papillary muscles. J Cardiovasc Pharm 1997, 29(5):670-675.
• [43]Tetsue Toda YK, Ryoichi Kawatsu : The 5-HT4 agonists cisapride, mosapride, and CJ-033466, a novel potent compound, exhibit different human ether-a-go-go-related gene (hERG)-blocking activities. J Pharmacol Sci 2007, 105:207-210.
• [44]Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Muller-Lissner S, Quigley EMM, Schuurkes J, De Maeyer JH, Stanghellini V: Systematic review: cardiovascular safety profile of 5-HT4 agonists developed for gastrointestinal disorders. Aliment Pharm Ther 2012, 35(7):745-767.
• [45]Mushiroda T, Douya R, Takahara E, Nagata O: The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: Comparison with cisapride and mosapride citrate. Drug Metab Dispos 2000, 28(10):1231-1237.
• [46]Kirpotina LN, Khlebnikov AI, Schepetkin IA, Ye RD, Rabiet MJ, Jutila MA, Quinn MT: Identification of novel small-molecule agonists for human Formyl peptide receptors and pharmacophore models of their recognition. Mol Pharmacol 2010, 77(2):159-170.