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http://dx.doi.org/10.5352/JLS.2018.28.3.307

Pharmacological Comparison of Timosaponin A III on the 5-beta Reductase and Androgen Receptor via In Silico Molecular Docking Approach

Kim, Dong-Chan (Department of Biomedical Laboratory Science, Gimcheon University)

Publication Information

Journal of Life Science / v.28, no.3, 2018 , pp. 307-313 More about this Journal

Abstract

Alopecia cause psychological stress due to their effect on appearance. Thus, the global market size of the alopecia treatment products are growing quickly. Timosaponin A III is the well known active ingredient of Anemarrhenae Rhizoma. In this study, we investigated and compared the binding affinity of timosaponin A III with finasteride (5-beta reductase antagonist) and minoxidil (androgen receptor antagonist) on the target protein active site by in silico computational docking studies. The three dimensional crystallographic structure of 5-beta reductase (PDB ID : 3G1R) and androgen receptor (PDB ID: 4K7A) was obtained from PDB database. In silico computational autodocking analysis was performed using PyRx, Autodock Vina, Discovery Studio Version 4.5, and NX-QuickPharm option based on scoring functions. The timosaponin A III showed optimum binding affinity (docking energy) with 5-beta reductase as -12.20 kcal/mol as compared to the finasteride (-11.70 kcal/mol) and with androgen receptor as -9.00 kcal/mol as compared to the minoxidil (-7.40 kcal/mol). The centroid X, Y, Z grid position of the timosaponin A III on the 5-beta reductase was similar (overlap) to the finasteride, but the X, Y, Z centroid grid of the timosaponin A III on the androgen receptor was significantly far from the minoxidil centroid position. These results significantly indicated that timosaponin A III could be more potent antagonist to the 5-beta reductase and androgen receptor. Therefore, the extract of Anemarrhenae Rhizoma or timosaponin A III containing biomaterials can substitute the finasteride and minoxidil and can be applied to the alopecia protecting product and related industrial fields.

탈모증상은 겉으로 보이는 모습으로 인해 정신적인 스트레스로 작용한다. 그래서 탈모 방지관련 제품의 글로벌 시장 규모는 지속적으로 성장하고 있다. Timosaponin A III는 지모 추출물에서 발견되는 대표적인 saponin 계열의 생리 활성 효능 성분이다. 본 연구에서는 5-beta reductase 단백질 길항제(antagonist) finasteride, androgen receptor 단백질 길항제 minoxidil, 그리고 지모 추출물의 효능 성분 timosaponin A III의 각각의 타깃 단백질 활성 부위에 대한 친화도 분석 실험을 in silico 컴퓨터 분자결합 분석 방법을 통해 비교하였다. 5-beta reductase 및 androgen receptor 의 3차원 구조 정보는 PDB database (5-beta reductase PDB ID: 3G1R / androgen receptor PDB ID:4K7A)를 활용하였다. In silico 결합 분석을 수행하기 위해 PyRx, Autodock Vina, Discovery Studio Version 4.5, and NX-QuickPharm 프로그램을 각 분석 조건에 따라 활용하였다. 5-beta reductase 활성 부위에 대한 timosaponin A III의 최대 결합친화도는 -12.20 kcal/mol으로 나왔으며 이는 -11.70 kcal/mol으로 분석된 finasteride의 5-beta reductase 활성부위에 대한 결합 친화도 보다 훨씬 더 높고 효율적인 것으로 분석되었다. Androgen receptor 활성 부위에 대한 timosaponin A III의 최대결합친화도 또한 -9.00 kcal/mol으로 -7.40 kcal/mol의 minoxidil에 비하여 훨씬 우수한 결합친화도 값을 나타내었다. Finasteride와 timosaponin A III의 5-beta reductase 단백질 활성 부위에 대한 X,Y,Z Grid 값은 유사한 좌표로 분석되었으나 minoxidil과 timosaponin A III의 androgen receptor 활성 부위에 대한 X,Y,Z centroid grid 좌표는 상당한 거리를 두고 떨어져 있음이 확인 되었다. 즉, timosaponin A III는 minoxidil이 androgen receptor에 결합하는 부위와는 다른 부위에 결합하여 단백질 활성에 영향을 주는 것으로 사료되었다. 이상의 연구 결과들을 바탕으로 분석해 볼 때, 5-beta reductase 길항제 finasteride와 androgen receptor 길항제 minoxidil보다 지모 추출물 생리 활성 물질인 timosaponin A III가 보다 더 효율적인 길항제로 작용할 수 있음을 확인하였다. 결론적으로 지모 추출물 또는 timosaponin 계열이 함유된 효능 성분은 탈모 방지 효능 및 모발 건강 개선을 위한 의약품, 의약외품 및 신물질 연구 개발 분야에 효율적으로 활용할 수 있을 것으로 사료된다.

Keywords

Alopecia; Anemarrhenae Rhizoma; autodock; binding affinity; timosaponin A III;

Citations & Related Records

Reference

1	Bae, J. S., Park, H. S., Park, J. W., Li, S. H. and Chun, Y. S. 2012. Red ginseng and 20(S)-Rg3 control testosterone-induced prostate hyperplasia by deregulating androgen receptor signaling. J. Nat. Med. 66, 476-485. DOI
2	Drury, J. E., Di Costanzo, L., Penning, T. M. and Christianson, D. W. 2009. Inhibition of human steroid 5beta-reductase (AKR1D1) by finasteride and structure of the enzyme-inhibitor complex. J. Biol. Chem. 284, 19786-19790.
3	Rubio-Gonzalez, B., Juhasz, M., Fortman, J. and Mesinkovska, N. A. 2018. Pathogenesis and treatment options for chemotherapy- induced alopecia: a systematic review. Int. J. Dermatol. doi: 10.1111/ijd.13906. DOI
4	Shan, L., Wu, Y., Yuan, L., Zhang, Y., Xu, Y. and Li, Y. 2017. Rapid screening of chemical constituents in rhizoma anemarrhenae by UPLC-Q-TOF/MS combined with data postprocessing techniques. Evid. Based Complement. Alternat. Med. 2017, 4032820.
5	Thom, E. 2016. Stress and the hair growth cycle: cortisolinduced hair growth disruption. J. Drugs Dermatol. 15, 1001-1004.
6	Matsuda, H., Sato, N., Yamazaki, M., Naruto, S. and Kubo, M. 2001. Testosterone 5alpha-reductase inhibitory active constituents from Anemarrhenae Rhizoma. Biol. Pharm. Bull. 24, 586-587. DOI
7	Kim, D. C. 2017. Identification of quercetin as a potential band 3 protein antioxidant using ektacytometry and in silico molecular docking technology. Intl. J. Appl. Eng. Res. 12, 8812-8816.
8	Li, Y. C., Chiang, C. W., Yeh, H. C., Hsu, P. Y., Whitby, F. G., Wang, L. H. and Chan, N. L. 2008. Structures of prostacyclin synthase and its complexes with substrate analog and inhibitor reveal a ligand-specific heme conformation change. J. Biol. Chem. 283, 2917-2926. DOI
9	Lim, S., Othman, R., Yusof, R. and Heh, C. 2017. Rational drug discovery of HCV helicase inhibitor: Improved docking accuracy with multiple seedings of Autodock Vina and in situ minimization. Curr. Comput. Aided Drug Des. 13, 160-169. DOI
10	Trott, O. and Olson, A. J. 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-461.
11	Murata, K., Noguchi, K., Kondo, M., Onishi, M., Watanabe, N., Okamura, K. and Matsuda, H. 2012. Inhibitory activities of Puerariae Flos against testosterone 5alpha-reductase and its hair growth promotion activities. J. Nat. Med. 66, 158-165. DOI
12	Mysore, V. and Shashikumar, B. M. 2016. Guidelines on the use of finasteride in androgenetic alopecia. Indian J. Dermatol. Venereol. Leprol. 82, 128-134. DOI
13	Nian, H., Qin, L. P., Chen, W. S., Zhang, Q. Y., Zheng, H. C. and Wang, Y. 2006. Protective effect of steroidal saponins from rhizome of Anemarrhena asphodeloides on ovariectomy- induced bone loss in rats. Acta. Pharmacol. Sin. 27, 728-734. DOI
14	Rathnayake, D. and Sinclair, R. 2010. Male androgenetic alopecia. Expert. Opin. Pharmacother. 11, 1295-1304. DOI
15	Gupta, A. K., Carviel, J. and Abramovits, W. 2017. Treating alopecia areata: current practices versus new directions. Am. J. Clin. Dermatol. 18, 67-75.