Insights into designing the dual-targeted HER2/HSP90 inhibitors

Heat shock protein 90 (HSP90) and human epidermal growth factor receptor 2 (HER2) are two key cancer markers actively involved in several signal pathways for cancer cell growth. In this study, we focused on the designing of dual-targeted HSP and HER2 inhibitors. Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and pharmacophore analysis were employed for generating the activity prediction models. The results of CoMFA model showed highly predictive r2 value with 0.922 and 0.885 in HSP90 and HER2, respectively. In CoMSIA model, the r2 values were 0.967 and 0.936 in HSP90 and HER2, respectively. The contour maps of both targets showed that there were similar regions of bulky favored area. Additionally, the Hypogen results for HER2 showed high cost difference as 59.13 and r-value as 0.909. At the C2 position of the benzene ring, the HER2 model favored steric bulkier substitutes more than HSP90. The Hypogen results for HSP90 also showed reliable values in cost difference, 85.82 and r-value, 0.902. Overall, we investigated the significances of QSAR models and pharmacophore features for designing the HER2/HSP90 dual-targeted inhibitors.