No abstract

No abstract

It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb ®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors Open Access *Equal contribution.

Human sodium-glucose cotransporter 2 (hSGLT2) is a membrane protein responsible for glucose reabsorption from the glomerular filtrate in the proximal tubule. Inhibition of hSGLT2 has been regarded as a brand new therapeutic approach for the treatment of type 2 diabetes mellitus (T2DM) due to its non-insulin related characteristics with less side effects. Current commercially available hSGLT2 inhibitors are all C-glycoside inhibitors. Previous studies have reported that N-glycoside inhibitors have better potential to serve as new drugs due to their good metabolic stability. In addition, non-glycoside inhibitors have been shown to exhibit the capability to overcome the existing problems of current glycoside inhibitors, including low tissue permeability, poor stability and short serum half-time. Here, we aimed to discover novel N-glycoside and non-glycoside hSGLT2 inhibitors by a combination of several computational approaches. A ligand-based pharmacophore model was generated, well validated and subsequently utilized as a 3D query to identify novel hSGLT2 inhibitors from National Cancer Institute (NCI) and Traditional Chinese Medicine (TCM) databases. Finally, one N-glycoside (NSC679207) and one non-glycoside (TCM_Piperenol_A) hSGLT2 inhibitors were successfully identified, which were proven to exhibit excellent binding affinities, pharmacokinetic properties and less toxicity than the commercially available hSGLT2 inhibitor, canagliflozin, via molecular docking, ADMET prediction, molecular dynamics (MD) simulations and binding free energy calculations. All together, our results strongly suggest that these two compounds have great potential to serve as novel hSGLT2 inhibitors for the treatment of T2DM and their efficacies may be further examined by a series of in vitro and/or in vivo bioassays.