Structure-activity relationship of coptis alkaloid bitterness inhibited by mPEG-PLLA

LI Pan1 QIU Min1 TIAN Yin1 KE Xiu-mei1 MA Hong-yan1 HAN Li1 YANG Ming2 ZHANG Ding-kun1

(1.State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan Province, China 611137)
(2.Key Laboratory of the Education Ministry for Modern TCM Preparation, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi Province, China 330004)
【Knowledge Link】Homologous modeling

【Abstract】Inhibition of bitterness is a significant measure to improve patients’ compliance and the clinical efficacy of traditional Chinese medicine (TCM) decoction. According to the characteristics of TCM decoction, such as high dispersion of bitter components, multi-component bitterness superposition, and strong instantaneous stimulation, the research group put forward a new strategy to inhibit bitterness in the early stage based on the self-assembly characteristics of amphiphilic substances in aqueous solution, in order to reduce the distribution of bitter components in real solution and achieve the purpose of bitter-masking. It was found that the bitter-masking effect of amphiphilic substances was different on the bitter compounds of various structures. Therefore, it was inferred that there might be a certain relationship between the bitterness inhibition effect and the substrate structure. In this paper, the interaction between mPEG-PLLA and five bitter alkaloids (palmatine, jatrorrhizine, berberine, epiberberine, and coptisine) in Coptidis Rhizoma was studied to explore the effect of substrate structure on the inhibition of bitterness. The sensory test of volunteers was used to determine the bitter-masking effect of mPEG-PLLA on Coptidis Rhizoma decoction and its main bitter alkaloids. The molecular docking and molecular force field were applied to locate the bitter groups and the bitter-masking parts. The relationship between the bitter strength and the structure was analyzed by the surface electrostatic potential of the bitter alkaloids, and the correlation between the bitter-masking effect and the structural parameters of the bitter components was explored by factor analysis, so as to clarify the structure-activity relationship of mPEG-PLLA in masking the bitterness of coptis alkaloids. It was found that mPEG-PLLA had significant taste masking effect on Coptidis Rhizoma decoction and the five alkaloids. The masking effect was obviously related to the structure of different alkaloids: the effect increased with the increase of the number of hydrogen donors, rotatable bonds, molecular weight, and hydrophobicity, and decreased with the increase of surface electrostatic potential, electrophilicity, and binding energy with bitter receptors. In this study, the influence of alkaloid structure of Coptidis Rhizoma on the bitter-masking effect of mPEG-PLLA was preliminarily elucidated, providing a scientific basis for better exerting the bitter-masking effect of amphiphilic block copolymers.

【Keywords】 mPEG-PLLA; copolymer micelles; bitter-masking; Coptidis Rhizoma; electrostatic potential; structural parameters;

【DOI】

【Funds】 National Natural Science Foundation of China (81803745) 2019-2021 Youth Talent Support Project of China Association of Chinese Medicine (2019-QNRC2-B05) Outstanding Young Scientific and Technological Talent Project of Science & Technology Department of Sichuan Province (2019JDJQ0007)

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    References

    [1] LIU B B, JIAN H, TIAN J M, et al. Research progress and problem analysis on flavoring and taste masking technology for traditional Chinese medicine [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2016, 22 (16): 229 (in Chinese).

    [2] LI X L, ZHANG Y, CHEN P J, et al. Study on superposition law of drug bitterness based on tongue taste evaluation and electronic tongue evaluation [J]. China Journal of Chinese Materia Medica, 2019, 44 (23): 5134 (in Chinese).

    [3] KOUCHAK M, RAMEZANI Z, BAGHERI F. Preparation and evaluation of taste masking iron suspension: taking advantage of weak cationic exchange resin [J]. AAPS Pharm Sci Tech, 2018, 19 (2): 719.

    [4] LI P, TIAN Y, KE X M, et al. Amphiphilic block copolymers: a novel substance for bitter-masking in aqueous solutions [J]. Mol Pharm, 2020, 17 (5): 1586.

    [5] SIMÕES S M, FIGUEIRAS A R, VEIGA F, et al. Polymeric micelles for oral drug administration enabling locoregional and systemic treatments [J]. Expert Opin Drug Deliv, 2015, 12 (2): 297.

    [6] Chinese Pharmacopoeia Commission. Chinese Pharmacopoeia. Volume Ⅰ[S]. Beijing: China Medical Science Press, 2015 (in Chinese).

    [7] ZHANG C G, TANG J Y, YU C C, et al. Extraction, purification and determination of five alkaloids in Rhizome Coptidis [J]. Modern Chinese Medicine, 2018, 20 (9): 1146 (in Chinese).

    [8] LIANG X G, WU F, WANG Y J, et al. Research on bitter components from Coptis chinensis based on electronic tongue [J]. China Journal of Chinese Materia Medica, 2014, 39 (17): 3326 (in Chinese).

    [9] BORRELLI M P, SETACCI F, DE DONATO G, et al. Patient discomfort during carotid artery stenting: a comparison study between iodixanol versus iopamidol [J]. Ann Vasc Surg, 2017, 39: 167.

    [10] NAKAMURA H, UCHIDA S, SUGIURA T, et al. The prediction of the palatability of orally disintegrating tablets by an electronic gustatory system [J]. Int J Pharm, 2015, 493 (1/2): 305.

    [11] LI P, HAN X, LIN J Z, et al. Application and development of volunteer sensory test in drug taste evaluation [J]. Chinese Pharmaceutical Journal, 2017, 52 (22): 1971 (in Chinese).

    [12] CHIAPPETTA DA, FACORRO G, DE CELIS E R, et al. Synergistic encapsulation of the anti-HIV agent efavirenz within mixed poloxamine/poloxamer polymeric micelles [J]. Nanomedicine, 2011, 7: 624.

    [13] HAN X, JIANG H, HAN L, et al. A novel quantified bitterness evaluation model for traditional Chinese herbs based on an animal ethology principle [J]. Acta Pharm Sin B, 2018, 8 (2): 209.

    [14] MEYERHOF W, BATRAM C, KUHN C, et al. The molecular receptive ranges of human TAS2R bitter taste receptors [J]. Chem Senses, 2010, 35 (2): 157.

    [15] LI X H, SU J S, LIU X H, et al. Correlation study on Tibetan medicine Pterocephalus hookeri of bitter taste receptors based on molecular docking technology [J]. China Journal of Chinese Materia Medica, 2019, 44 (15): 3157 (in Chinese).

    [16] HAN Y Q, XU J, GONG S X, et al. Approaches and methods of property-flavour material basis of Chinese materia medica based on molecular docking technology of taste and olfactory receptors [J]. Chinese Traditional and Herbal Drugs, 2018, 49 (1): 14 (in Chinese).

    [17] KOHN W, SHAM L J. Self-consistent equations including exchange and correlation effects [J]. J Phys Rev, 1965, 140: A1133.

    [18] ZHAO Y, TRUHLAR D G. Design of density functionals that are broadly accurate for thermochemistry, thermochemical kinetics, and nonbonded interactions [J]. J Phys Chem A, 2005, 109 (25): 5656.

    [19] BARONE V, COSSI M. Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model [J]. J Phys Chem A, 1998, 102: 1995.

    [20] COSSI M, REGA N, SCALMANI G, et al. Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model [J]. J Comput Chem, 2003, 24 (6): 669.

    [21] LI Y, ZHANG T, LIU Q, et al. PEG-derivatized dual-functional nanomicelles for improved cancer therapy [J]. Front Pharmacol, 2019, 10: 808.

    [22] XIAO Z, ZENG Z W, ZHOU G L, et al. Recent advances in PEG-PLA block copolymer nanoparticles [J]. Int J Nanomedicine, 2010, 5: 1057.

    [23] GAO M Q, REN H L, XIE C, et al. Preparation and in vitro characterization of paclitaxel-loaded mPEG-PLA polymer micelles [J]. Chinese Journal of New Drugs, 2017, 26 (16): 1948 (in Chinese).

    [24] LIU J J. Study on bitterness mechanism and bitter compounds [J]. Food Science and Technology, 2006, 31 (8): 21 (in Chinese).

    [25] ZHENG X Q, WU Z Y, JIN H W, et al. Characterization and comparative analysis of chemical libraries for drug discovery [J]. Acta Physico-Chimica Sinica, 2012, 28 (10): 2401 (in Chinese).

This Article

ISSN:1001-5302

CN: 11-2272/R

Vol 45, No. 13, Pages 3128-3135

July 2020

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Abstract

  • 1 Materials
  • 2 Methods and results
  • 3 Discussion
  • References