Structure-Activity Relationship Studies Based on 3D-QSAR CoMFA/CoMSIA for Thieno-Pyrimidine Derivatives as Triple Negative Breast Cancer Inhibitors

Abstract

Triple-negative breast cancer (TNBC) is defined as a kind of breast cancer that lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). This cancer accounts for 10-15% of all breast cancers and has the features of high invasiveness and metastatic potential. The treatment regimens are still lacking and need to develop novel inhibitors for therapeutic strategies. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, based on a series of forty-seven thieno-pyrimidine derivatives, were performed to identify the key structural features for the inhibitory biological activities. The established comparative molecular field analysis (CoMFA) presented a leave-one-out cross-validated correlation coefficient q² of 0.818 and a determination coefficient r² of 0.917. In comparative molecular similarity indices analysis (CoMSIA), a q² of 0.801 and an r² of 0.897 were exhibited. The predictive capability of these models was confirmed by using external validation and was further validated by the progressive scrambling stability test. From these results of validation, the models were determined to be statistically reliable and robust. This study could provide valuable information for further optimization and design of novel inhibitors against metastatic breast cancer.

Keywords: 3D-QSAR; CoMFA; CoMSIA; TNBC; VEGFR3; thieno-pyrimidine derivatives.

Figure 1

Inhibitors targeting VEGFRs.

Figure 2

Scatter plots of the actual versus predicted inhibitory activities for the CoMFA model; (a) The training set; (b) The test set.

Figure 3

Contour maps of CoMFA analysis with the most active compound 42 (left) and the least compound 20 (right). In each field, favored and disfavored areas are fixed with 80% and 20% contribution levels, respectively; (a,b) Steric field: favored regions are in green contours and disfavored regions are in yellow contours; (c,d) Electrostatic field: favored regions are in blue contours and disfavored regions are in red contours.

Figure 4

Scatter plots of the actual versus predicted inhibitory activities for the CoMSIA model; (a) The training set; (b) The test set.

Figure 5

Contour maps of CoMSIA with the most active compound 42 (left) and the least active compound 20 (right). In each field, favored and disfavored areas are fixed with 80% and 20% contribution levels, respectively; (a,b) Steric field: favored regions are in green contours and disfavored regions are in yellow contours; (c,d) Electrostatic field: favored regions are in blue contours and disfavored regions are in red contours; (e,f) Hydrophobic field: favored regions are in orange contours and disfavored regions are in yellow contours; (g,h) Hydrogen bond donor field: favored regions are in cyan contours and disfavored regions are in purple contours; (i,j) Hydrogen bond acceptor field: favored regions are in magenta contours and disfavored regions are in red contours.

Figure 6

(a) The structure of the most active compound 42 as the template including the maximum common substructure in red; (b) The alignment of the training and test sets used in the 3D-QSAR model.

Figure 7

The novel design strategy information obtained from the 3D-QSAR study.