EFFECT OF NON-SYNONYMOUS SINGLE-NUCLEOTIDE POLYMORPHISM OF HUMAN CARBOXYL ESTERASE 1 ON THE BIOACTIVATION OF DABIGATRAN ETEXILATE

GOUTHAM YERRAKULA; SAMUEL GIDEON GEORGE; KRISHNA KUMAR D.; ANAND VIJAYA KUMAR P. R.; JAWAHAR N.; SENTHIL VENKATACHALAM

doi:10.22159/ijap.2022v14i5.44682

Authors

GOUTHAM YERRAKULA Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India
SAMUEL GIDEON GEORGE Department of Pharmacy Practice, Krupanidhi College of Pharmacy, Bangalore
KRISHNA KUMAR D. Department of Pharmacy Practice, The Erode College of Pharmacy and Research Institute, Erode
ANAND VIJAYA KUMAR P. R. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India
JAWAHAR N. Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India
SENTHIL VENKATACHALAM Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India https://orcid.org/0000-0003-3110-1229

DOI:

https://doi.org/10.22159/ijap.2022v14i5.44682

Keywords:

Dabigatran etexilate, Carboxylesterase 1, Pharmacogenomics, Bioavailability, Genetic polymorphisms

Abstract

Objective: Dabigatran Etexilate is an oral acting direct thrombin inhibitor used for prophylaxis of cardioembolic events in non-valvular atrial fibrillation patients. Genetic polymorphisms in hCES1 gene can significantly alter the conformations of the enzyme drug binding and impair the catalytic ability. Hence this study is performed to determine the effect of single nucleotide variations on dabigatran activation by hCES1.

Methods: Energy minimization was performing using YASARA server. Dihedral angles of the modeled targets were visualized using Ramachandran Plot. We performed molecular docking analysis with Autodock 4.2. Three-dimensional grid was constructed using Autogrid. Docked complexes were visualized using Pymol Viewer.

Results: Significant differences in the binding energy and conformations of Dabigatran in the active site of the target was observed between the Ser75Asn, Ala158Val, Asp203Glu, Ala269Ser and Thr290Met variants. The catalytic triad was completely or partially disrupted in the variants suggestive of altered enzyme activity.

Conclusion: The binding energy of Dabigatran with the mutant (79Ala, 221Ala, 354Ala and 468Ala) was found to be less than that of the wild type. This indicates that the presence of functional non-synonymous polymorphism in the hCES1 significantly alters the binding of Dabigatran. Hence patients who have this SNP (332G>A, 581C>T, 717C>A, 913C>T, 977C>T) would have decreased hCES1 function, which would result in therapeutic failure or sub-therapeutic drug action.

Downloads

Download data is not yet available.

References

Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011;123(2):131-6. doi: 10.1161/ CIRCULATIONAHA.110.977546, PMID 21200007.

Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND. Effectiveness and safety of dabigatran, Rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016;5(6):e003725. doi: 10.1161/JAHA.116.003725, PMID 27412905.

Gouin Thibault I, Delavenne X, Blanchard A, Siguret V, Salem JE, Narjoz C. Interindividual variability in dabigatran and rivaroxaban exposure: contribution of ABCB 1 genetic polymorphisms and interaction with clarithromycin. J Thromb Haemost. 2017;15(2):273-83. doi: 10.1111/jth.13577, PMID 27893182.

Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. 2009;15Suppl 1:9S-16S. doi: 10.1177/1076029609343004, PMID 19696042.

Laizure SC, Parker RB, Herring VL, Hu ZY. Identification of carboxylesterase-dependent dabigatran etexilate hydrolysis. Drug Metab Dispos. 2014;42(2):201-6. doi: 10.1124/dmd.113.054353, PMID 24212379.

Shi J, Wang X, Nguyen JH, Bleske BE, Liang Y, Liu L. Dabigatran etexilate activation is affected by the CES1 genetic polymorphism G143E (rs71647871) and gender. Biochem Pharmacol. 2016;119:76-84. doi: 10.1016/j.bcp.2016.09.003, PMID 27614009.

Zhu HJ, Patrick KS, Yuan HJ, Wang JS, Donovan JL, DeVane CL. Two CES1 gene mutations lead to dysfunctional carboxylesterase 1 activity in man: clinical significance and molecular basis. Am J Hum Genet. 2008;82(6):1241-8. doi: 10.1016/j.ajhg.2008.04.015, PMID 18485328.

Nelveg Kristensen KE, Bie P, Ferrero L, Bjerre D, Bruun NE, Egfjord M. Pharmacodynamic impact of carboxylesterase 1 gene variants in patients with congestive heart failure treated with angiotensin-converting enzyme inhibitors. PLOS ONE. 2016;11(9):e0163341. doi: 10.1371/journal.pone.0163341, PMID 27662362.

Wang X, Wang G, Shi J, Aa J, Comas R, Liang Y, et al. CES1 genetic variation affects the activation of angiotensin-converting enzyme inhibitors. Pharmacogenomics J. 2016;16(3):220-30. doi: 10.1038/tpj.2015.42, PMID 26076923.

Bjerre D, Berg Rasmussen H, Indices Consortium TT. Novel approach for CES1 genotyping: integrating single nucleotide variants and structural variation. Pharmacogenomics. 2018;19(4):349-59. doi: 10.2217/pgs-2016-0145, PMID 29457755.

Suzaki Y, Uemura N, Takada M, Ohyama T, Itohda A, Morimoto T. The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans. Eur J Clin Pharmacol. 2013;69(1):21-30. doi: 10.1007/s00228-012-1315-5, PMID 22673926.

Kaur K, Kaur P, Mittal A, Nayak SK, Khatik GL. Design and molecular docking studies of novel antimicrobial peptides using autodock molecular docking software. Asian J Pharm Clin Res. 2017;10(16):28-31. doi: 10.22159/ajpcr.2017.v10s4.21332.

Sultana MN, Qureshi SY, Fatima I, Jabeen W, Obaid M. A prospective observational study on the assessment of potential drug-drug interactions and management of post-complications in stroke patients at a tertiary care teaching hospital. Int J Pharm Pharm Sci. 2021 Nov;13(11):8-14. doi: 10.22159/ijpps.2021v13i11.42527.

Sharma A, Kunwar S, Vaishali, Agarwal V, Singh C, Sharma MD. Molecular docking: an explanatory approach in structure-based drug designing and discovery. Int J Pharm Pharm Sci. 2021 Jun;13(6):6-12. doi: 10.22159/ijpps.2021v13i6.40830.

Vene N, Mavri A, Gubensek M, Tratar G, Vizintin Cuderman T, Pohar Perme M. Risk of thromboembolic events in patients with non-valvular atrial fibrillation after dabigatran or rivaroxaban discontinuation– data from the ljubljana registry. PLOS ONE. 2016;11(6):e0156943. doi: 10.1371/journal.pone.0156943, PMID 27280704.

Wang D, Zou L, Jin Q, Hou J, Ge G, Yang L. Human carboxylesterases: a comprehensive review. Acta Pharm Sin B. 2018;8(5):699-712. doi: 10.1016/j.apsb.2018.05.005, PMID 30245959.

Bencharit S, Morton CL, Hyatt JL, Kuhn P, Danks MK, Potter PM. Crystal structure of human carboxylesterase 1 complexed with the Alzheimer’s drug tacrine: from binding promiscuity to selective inhibition. Chem Biol. 2003;10(4):341-9. doi: 10.1016/s1074-5521(03)00071-1, PMID 12725862.

Vistoli G, Pedretti A, Mazzolari A, Testa B. Homology modeling and metabolism prediction of human carboxylesterase-2 using docking analyses by GriDock: a parallelized tool based on AutoDock 4.0. J Comput Aided Mol Des. 2010;24(9):771-87. doi: 10.1007/s10822-010-9373-1, PMID 20623318.

Jendele L, Krivak R, Skoda P, Novotny M, Hoksza D. PrankWeb: a web server for ligand binding site prediction and visualization. Nucleic Acids Res. 2019;47(W1):W345-9. doi: 10.1093/nar/gkz424, PMID 31114880.

Krieger E, Koraimann G, Vriend G. Increasing the precision of comparative models with YASARA NOVA-a self-parameterizing force field. Proteins. 2002;47(3):393-402. doi: 10.1002/prot.10104.

Nzabonimpa GS, Rasmussen HB, Brunak S, Taboureau O, INDICES consortium. Investigating the impact of missense mutations in hCES1 by in silico structure-based approaches. Drug Metab Pers Ther. 2016;31(2):97-106. doi: 10.1515/dmpt-2015-0034, PMID 26900165.

Wang X, Rida N, Shi J, Wu AH, Bleske BE, Zhu HJ. A comprehensive functional assessment of carboxylesterase 1 nonsynonymous polymorphisms. Drug Metab Dispos. 2017;45(11):1149-55. doi: 10.1124/dmd.117.077669, PMID 28838926.

Chen F, Zhang B, Parker RB, Laizure SC. Clinical implications of genetic variation in carboxylesterase drug metabolism. Expert Opin Drug Metab Toxicol. 2018;14(2):131-42. doi: 10.1080/17425255.2018.1420164, PMID 29264996.

Her L, Zhu HJ. Carboxylesterase 1 and precision pharmacotherapy: pharmacogenetics and nongenetic regulators. Drug Metab Dispos. 2020;48(3):230-44. doi: 10.1124/dmd.119.089680, PMID 31871135.

Kajy M, Mathew A, Ramappa P. Treatment failures of direct oral anticoagulants. Lippincott Williams & Wilkins; 2021.