2. Academic Validation
  3. A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity

A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity

  • Comput Struct Biotechnol J. 2021 Jun 6:19:3437-3450. doi: 10.1016/j.csbj.2021.06.011.
Cai Lu 1,  Lu Fan 2,  Peng-Fei Zhang 1,  Wei-Wei Tao 3,  Cheng-Bin Yang 1,  Er-Xin Shang 1,  Fei-Yan Chen 3,  Chun-Tao Che 4,  Hai-Bo Cheng 5,  Jin-Ao Duan 1,  Ming Zhao 1
Affiliations

Affiliations

  • 1 Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 School of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
  • 5 Collaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing 210023, China.
PMID: 34194669 DOI: 10.1016/j.csbj.2021.06.011
Abstract

Pancreatic Cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic Cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A's action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-C[bond, double bond]O, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic Cancer progression, and as a novel lead compound for pancreatic Cancer therapy.

Keywords

Binding affinity; Bruceine A; Molecular simulations; P38α MAPK activator; Phosphoproteomic; Quassinoids.

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