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.Materials and 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.Conclusion: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.SUMMARY 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.

Botanicals as Modulators of Neuroplasticity: Focus on BDNF

“…In senescence-accelerated mice-prone 8 (SAMP8), a model characterized by the early onset of learning and memory deficits along with overproduction of soluble amyloid peptide in the brain, the chronic treatment with green tea catechins (GTC) (0.05% and 0.1% in drinking water for 6 months) restored the reduction of mBDNF levels in the hippocampus and prevented the learning impairment of SAMP8 mice [ 79 ]. Finally, 4 months of EC administration (50 mg/kg daily in drinking water) normalized the low levels of BDNF protein in the hippocampus of 8-month-old APP/PS1 mice, without affecting escape latency in MWM [ 80 ].…”

Boesenbergia Pandurata as an Anti-Breast Cancer Agent: Molecular Docking and ADMET Study

“…However, in silico studies on HER2 require immediate attention because, so far, no receptor crystals have been reported that bind to compounds that have been used in therapy, such as lapatinib. Currently, the most widely used crystals for the development of HER2 inhibitors are those that bind to experimental drugs, such as 2-{2-[4-({5-chloro-6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}amino)-5hpyrrolo[3,2-D]pyrimidin-5-yl]ethoxy}ethanol in PDB 3PP0 and TAK-285 in PDB 3RCD, as reported by Shi et al [55] and Yousuf et al [56]. Furthermore, in studies conducted by Li et al [53] and Yang et al [54], lapatinib was used as a reference ligand for these receptors.…”

Systems biology approaches based discovery of a small molecule inhibitor targeting both c-Met/PARP-1 and inducing cell death in breast cancer

“…For example, Foretinib, a multi-target kinases inhibitor against both c-Met and VEGFR2, is currently under phase II trials [39]. Cabozantinib, an orally bioavailable tyrosine kinase inhibitor which targeting a number of tyrosine kinases, including RET, KIT and AXL, c-Met, etc., has been approved for the treatment of patients with progressive, metastatic medullary thyroid carcinoma [40,41]. However, novel inhibitors are still urgently waited for anti c-Met therapy in context of breast cancer.…”