|
|
|
|
|
|
| Spectral Study on Anticoagulation Mechanism of Dabigatran |
| GONG Meng-jie1, HAI Ying1, LÜ Kai-wen1, GU Hong-bin2*, ZU Li-li1* |
1. College of Chemistry, Beijing Normal University, Beijing 100875, China
2. Department of Vascular Surgery, Strategic Support Force Characteristic Medical Center of PLA, Beijing 100101, China
|
|
|
|
|
Abstract Dabigatran etexilate (DE) is a new oral anticoagulant drug used to prevent non valvular atrial fibrillation stroke and vascular embolism. DE itself has no pharmacological activity. Its active component is Dabigatran (DAB), the product of DE by catalyzed hydrolysis in plasma and liver. However, the interaction mechanism between the polar groups of DAB and thrombin is still unclear, especially in physiological conditions, although the drug has already been used for clinical treatment. No specific reversal agent has been found for dabigatran.This work used steady-state and time-resolved fluorescence spectroscopy methods to study the interaction between DAB and thrombin in pH 7.4 phosphate buffer. A combination of dynamic and static fluorescence quenching of thrombin when in contact with DAB wasobserved, suggesting that the electrostatic effect between thrombin and the benzamidine group of DAB was the key factor of a fast and effective formation of the DAB-thrombin complex. The molecular conformation of DAB when in interaction with thrombin was studied by molecular docking simulation and the effect of DAB polar groups on the binding energy was investigated. By comparing the fluorescence spectra and molecular docking simulation results of the interaction between thrombin and dabigatran ester (DE, esterification of both DAB polar groups), dabigatran ethyl ester (DAE, esterification of DAB carboxylic group), and dabigatran hexyl ester (DAH, esterification of DAB benzamidine group), the role of polar groups in the combination of dabigatran and thrombin was further verified. Steady-state and transient fluorescence spectra of DAB and DE interacting with bovine serum albumin (BSA) under physiological pH conditions were also obtained,confirming that the polar groups of DAB play an important role in the selective binding of DAB with thrombin. The results provide theoretical and experimental bases for improving the drug efficiency and finding reversal agents.
|
|
Received: 2022-11-16
Accepted: 2023-07-24
|
|
|
|
Corresponding Authors:
GU Hong-bin, ZU Li-li
E-mail: hongbingu@hotmail.com; zull@bnu.edu.cn
|
|
[1] Salem J, Sabouret P, Funck-Brentano C, et al. Fundamental & Clinical Pharmacology, 2015, 29(1): 10.
[2] Shnayder N A, Petrova M M, Shesternya P A, et al. Biomedicines, 2021, 9(5): 451.
[3] Diener H C, Sacco R L, Easton J D, et al. New England Journal of Medicine, 2019, 380(20): 1906.
[4] Ruff C T, Giugliano R P, Braunwald E, et al. The Lancet, 2014, 383(9921): 955.
[5] Hauel N H, Nar H, Priepke H, et al. Journal of Medicinal Chemistry, 2002, 45: 1757.
[6] Laizure S C, Parker R B, Herring V L, et al. Drug Metabolism and Disposition, 2014, 42(2): 201.
[7] Levy J H, Douketis J, Weitz J I, Nature Reviews Cardiology, 2018, 15: 273.
[8] Yang H, Liu Q, Gao X, et al. European Journal of Medicinal Chemistry, 2017, 126: 799.
[9] Naik R S, Pawar S K, Tandel R D, et al. Journal of Molecular Liquids, 2018, 251: 119.
[10] Michaelis S, Marais A, Schrey A K, et al. Journal of Medicinal Chemistry, 2012, 55: 3934.
[11] Remko M, Broer R, Remková A, RSC Advances, 2014, 4: 8072.
[12] Fuglestad B, Gasper P M, Tonelli M, et al. Biophysical Journal, 2012, 103: 79.
[13] Meng X, Zhang H, Mezei M, et al. Current Computer-Aided Drug Design, 2011, 7(2): 146.
[14] Wang Z, Sun H, Yao X, et al. Physical Chemistry Chemical Physics, 2016, 18(18): 12964.
[15] Burley S K, Bhikadiya C, Bi C, et al. Nucleic Acids Research, 2023, 51(D1): D488.
[16] Frisch M J, Trucks G W, Schlegel H B, et al. Gaussian 16 Rev. A. 03, Gaussian, Inc., Wallingford, CT, 2016.
[17] Morris G M, Huey R, Lindstrom W, et al. Journal of Computational Chemistry, 2009, 30(16): 2785.
[18] Trott O, Olson A J. Journal of Computational Chemistry, 2010, 31(2): 455.
[19] Baerga-Ortiz A, Rezaie A R, Komives E A. Journal of Molecular Biology, 2000, 296: 651.
[20] Borisevich N, Loznikova S, Sukhodola A, et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2013, 104: 158.
[21] Huntington J A. Thrombosis and Haemostasis, 2014, 111: 583.
[22] Coburn C A. Expert Opinion on Therapeutic Patents, 2001, 11: 721.
[23] Schwienhorst A. Cellular and Molecular Life Sciences, 2006, 63: 2773.
[24] Simone G De, Pasquadibisceglie A, Masi A di, et al. Journal of Molecular Recognition, 2021, 34(3): e2877.
|
| [1] |
YANG Wan-qi1, 2, LI Zhi-qi1, 3, LI Fu-sheng1, 2*, LÜ Shu-bin1, 2, FAN Jia-jing1, 2. A Combined CARS and 1D-CNN Method for the Analysis of Heavy Metals Exceedances in Soil by XRF Spectroscopy[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(03): 670-674. |
| [2] |
ZHANG Jing, WANG Hong-hui, JIN Liang, LIAO Ying-min, LI Heng. Effects of 9-Hydroxyphenanthrene on α-Glucosidase Activity and Their Binding Interactions[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(02): 398-405. |
| [3] |
CHEN Peng1, 2, LU Feng2, ZHAO Yun-li1*. Intact-Cell Detection of Haloacid Dehalogenase Activity Based on
Fluorescence Spectroscopy[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(02): 413-418. |
| [4] |
TENG Jing1, 2, SHI Yao2, LI Hui-quan2, 3*, LIU Zuo-hua1*, LI Zhi-hong2, HE Ming-xing2, 4, ZHANG Chen-mu2. The Mechanism of Moisture Influence and Correction of Electroplating Sludges Testing With EDXRF[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(02): 419-425. |
| [5] |
WANG Hai-zhen1, 2, 3, GUO Jian-fen1, 2, 3*, ZHANG Lei1, 2, 3, LIN Hao1, 2, 3, LIN Jing-wen1, XIONG De-cheng1, 2, 3, CHEN Shi-dong1, 2, 3, YANG Yu-sheng1, 2, 3. Composition and Spectral Characteristics of Soil Dissolved Organic Matter Leachate From Different Planted Tree Species[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(02): 490-496. |
| [6] |
WANG Chong1, REN Zhong-xuan1, 2, LI Dong-dong1, SHE Jiang-bo2. Enhanced Up-Conversion Emission of NaGdF4：Yb3+/Eu3+Crystal via Li+ Doping for Anti-Counterfeiting Application[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(02): 497-503. |
| [7] |
GU Yi-lu1, 2，PEI Jing-cheng1, 2*，ZHANG Yu-hui1, 2，YIN Xi-yan1, 2，YU Min-da1, 2, LAI Xiao-jing1, 2. Gemological and Spectral Characterization of Yellowish Green Apatite From Mexico[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(01): 181-187. |
| [8] |
HAN Xue1, 2, LIU Hai1, 2, LIU Jia-wei3, WU Ming-kai1, 2*. Rapid Identification of Inorganic Elements in Understory Soils in
Different Regions of Guizhou Province by X-Ray
Fluorescence Spectrometry[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(01): 225-229. |
| [9] |
LEI Hong-jun1, YANG Guang1, PAN Hong-wei1*, WANG Yi-fei1, YI Jun2, WANG Ke-ke2, WANG Guo-hao2, TONG Wen-bin1, SHI Li-li1. Influence of Hydrochemical Ions on Three-Dimensional Fluorescence
Spectrum of Dissolved Organic Matter in the Water Environment
and the Proposed Classification Pretreatment Method[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2024, 44(01): 134-140. |
| [10] |
WANG Hong-jian1, YU Hai-ye1, GAO Shan-yun1, LI Jin-quan1, LIU Guo-hong1, YU Yue1, LI Xiao-kai1, ZHANG Lei1, ZHANG Xin1, LU Ri-feng2, SUI Yuan-yuan1*. A Model for Predicting Early Spot Disease of Maize Based on Fluorescence Spectral Analysis[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2023, 43(12): 3710-3718. |
| [11] |
CHENG Hui-zhu1, 2, YANG Wan-qi1, 2, LI Fu-sheng1, 2*, MA Qian1, 2, ZHAO Yan-chun1, 2. Genetic Algorithm Optimized BP Neural Network for Quantitative
Analysis of Soil Heavy Metals in XRF[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2023, 43(12): 3742-3746. |
| [12] |
SONG Yi-ming1, 2, SHEN Jian1, 2, LIU Chuan-yang1, 2, XIONG Qiu-ran1, 2, CHENG Cheng1, 2, CHAI Yi-di2, WANG Shi-feng2，WU Jing1, 2*. Fluorescence Quantum Yield and Fluorescence Lifetime of Indole, 3-Methylindole and L-Tryptophan[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2023, 43(12): 3758-3762. |
| [13] |
YANG Ke-li1, 2, PENG Jiao-yu1, 2, DONG Ya-ping1, 2*, LIU Xin1, 2, LI Wu1, 3, LIU Hai-ning1, 3. Spectroscopic Characterization of Dissolved Organic Matter Isolated From Solar Pond[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2023, 43(12): 3775-3780. |
| [14] |
LI Xiao-li1, WANG Yi-min2*, DENG Sai-wen2, WANG Yi-ya2, LI Song2, BAI Jin-feng1. Application of X-Ray Fluorescence Spectrometry in Geological and
Mineral Analysis for 60 Years[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2023, 43(10): 2989-2998. |
| [15] |
XUE Fang-jia, YU Jie*, YIN Hang, XIA Qi-yu, SHI Jie-gen, HOU Di-bo, HUANG Ping-jie, ZHANG Guang-xin. A Time Series Double Threshold Method for Pollution Events Detection in Drinking Water Using Three-Dimensional Fluorescence Spectroscopy[J]. SPECTROSCOPY AND SPECTRAL ANALYSIS, 2023, 43(10): 3081-3088. |
|
|
|
|
