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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.00801

Polypharmacology of berberine based on multi-target binding motifs

 Ming Chu1, 2*, Xi Chen1, Likai Guo1, 2,  Qianqian Wang1, 2, Zirui Gao1, Jiarui Kang3, Mingbo Zhang4, Jinqiu Feng1, 2, Qi Guo1, Binghua Li1, 2, Chengrui Zhang1, 2, Xueyuan Guo1, 2, Zhengyun Chu4 and Yuedan Wang1, 2
  • 1School of Basic Medical Sciences, Peking University Health Science Centre, China
  • 2Key Laboratory of Medical Immunology, National Health and Family Planning Commission (China), China
  • 3Pathology, First Affiliated Hospital of Chinese PLA General Hospital, China
  • 4Pharmacy, Liaoning University of Traditional Chinese Medicine, China

Background: Polypharmacology is emerging as the next paradigm in drug discovery. However, considerable challenges still exist for polypharmacology modeling. In this study, we developed a rational design to identify highly potential targets (HPTs) for polypharmacological drugs, such as berberine.
Methods and Results: All the proven co-crystal structures locate berberine in the active cavities of a redundancy of aromatic, aliphatic, and acidic residues. The side chains from residues provide hydrophobic and electronic interactions to aid in neutralization for the positive charge of berberine. Accordingly, we generated multi-target binding motifs (MBM) for berberine, and established a new mathematical model to identify HPTs based on MBM. Remarkably, the berberine MBM was embodied in 13 HPTs, including beta-secretase 1 (BACE1) and amyloid-β1-42 (Aβ1-42). Further study indicated that berberine acted as a high-affinity BACE1 inhibitor and prevented Aβ1-42 aggregation to delay the pathological process of Alzheimer’s disease.
Conclusion: Here, we proposed a MBM-based drug-target space model to analyze the underlying mechanism of multi-target drugs against polypharmacological profiles, and demonstrated the role of berberine in Alzheimer’s disease. This approach can be useful in derivation of rules, which will illuminate our understanding of drug action in diseases.

Keywords: Berberine, polypharmacology, multi-target binding motifs, drug-target space, Alzheimer’s disease, BACE1, amyloid beta1-42

Received: 21 Apr 2018; Accepted: 03 Jul 2018.

Edited by:

Vincent Kam Wai Wong, Macau University of Science and Technology, Macau

Reviewed by:

Onat Kadioglu, Johannes Gutenberg University, Institute of Pharmacy and Biochemistry, Pharmaceutical Biology Department
Dik-Lung Ma, Hong Kong Baptist University, Hong Kong  

Copyright: © 2018 Chu, Chen, Guo, Wang, Gao, Kang, Zhang, Feng, Guo, Li, Zhang, Guo, Chu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Ming Chu, Peking University Health Science Centre, School of Basic Medical Sciences, Beijing, 100191, China,