title: Discovery of Novel Human Epidermal Growth Factor Receptor-2 Inhibitors by Structure-based Virtual Screening.
abstract: BACKGROUND
  Human epidermal growth factor receptor-2 (HER2) is a trans-membrane receptor like protein, and aberrant signaling of HER2 is implicated in many human cancers, such as ovarian cancer, gastric cancer, and prostate cancer, most notably breast cancer. Moreover, it has been in the spotlight in the recent years as a promising new target for therapy of breast cancer.
  
  
  OBJECTIVE
  Since virtual screening has become an integral part of the drug discovery process, it is of great significant to identify novel HER2 inhibitors by structure-based virtual screening.
  
  
  METHODS
  In this study, we carried out a series of elegant bioinformatics approaches, such as virtual screening and molecular dynamics (MD) simulations to identify HER2 inhibitors from Food and Drug Administration-approved small molecule drug as potential "new use" drugs.
  
  
  RESULTS
  Molecular docking identified top 10 potential drugs which showed spectrum affinity to HER2. Moreover, MD simulations suggested that ZINC08214629 (Nonoxynol-9) and ZINC03830276 (Benzonatate) might exert potential inhibitory effects against HER2-targeted anti-breast cancer therapeutics.
  
  
  CONCLUSIONS
  Together, our findings may provide successful application of virtual screening studies in the lead discovery process, and suggest that our discovered small molecules could be effective HER2 inhibitor candidates for further study.
  
  
  CONCLUSIONS
  A series of elegant bioinformatics approaches, including virtual screening and molecular dynamics (MD) simulations were took advantage to identify human epidermal growth factor receptor-2 (HER2) inhibitors. Molecular docking recognized top 10 candidate compounds, which showed spectrum affinity to HER2. Further, MD simulations suggested that ZINC08214629 (Nonoxynol-9) and ZINC03830276 (Benzonatate) in candidate compounds were identified as potential "new use" drugs against HER2-targeted anti-breast cancer therapeutics. Abbreviations used: HER2: Human epidermal growth factor receptor-2, FDA: Food and Drug Administration, PDB: Protein Database Bank, RMSDs: Root mean square deviations, SPC: Single point charge, PME: Particle mesh Ewald, NVT: Constant volume, NPT: Constant pressure, RMSF: Root-mean-square fluctuation.
authors.affiliation: Department of Basic Medicine, School of Medicine and Nursing, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610015, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Basic Medicine, School of Medicine and Nursing, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610015, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Bioinformatics, School of Life Sciences, Key Laboratory of Bio-resources, Ministry of Education, Sichuan University, Chengdu 610064, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.affiliation: Department of Basic Medicine, School of Medicine and Nursing, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610015, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Basic Medicine, School of Medicine and Nursing, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610015, China.
authors.forename: Xiao-Qian
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Department of Basic Medicine, School of Medicine and Nursing, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610015, China.
authors.forename: Li-Jia
authors.initials: LJ
authors.lastname: Cheng
authors.affiliation: Department of Basic Medicine, School of Medicine and Nursing, Sichuan Industrial Institute of Antibiotics, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610015, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
keywords: Drug development; human epidermal growth factor receptor-2; kinase; kinase inhibitor; virtual screening