Exploring structural features of EGFR–HER2 dual inhibitors as anti-cancer agents using G-QSAR approach. (4th May 2019)

• Record Type: Journal Article
• Authors: Fatima, Shehnaz; Agarwal, Subhash Mohan
• Is Part Of: Journal of receptor and signal transduction research. Volume 39:Number 3(2019)
• Page Start: 243
• Page End: 252
• Publication Date: 2019-05-04
• Subjects: Dual inhibitors -- EGFR -- HER2 -- QSAR -- Williams plot; Cell receptors -- Periodicals; Cellular signal transduction -- Periodicals; 571.6
• DOI: 10.1080/10799893.2019.1660896
• Languages: English
• ISSNs: 1079-9893

Abstract

Abstract: Simultaneous inhibition of EGFR and HER2 by dual-targeting inhibitors is an established anti-cancer strategy. Therefore, a recent trend in drug discovery involves understanding the features of such dual inhibitors. In this study, three different G-QSAR models were developed corresponding to individual EGFR, HER2 and the dual-model for both receptors. The dual-model provided site-specific information wherein (i) increasing electronegative character and higher index of saturated carbon at R4 position; (ii) presence of chlorine atom at R2 position; (iii) decreasing alpha modified shape index at R1 and R3 positions; and (iv) less electronegativity at R2 position; were found important for enhancing the dual activity. Also, comparison of dual-model with the EGFR/HER2 individual models revealed that it incorporates the properties of both models and, thus, represents a combination of EGFR/HER2. Further, fragment analysis revealed that R2 and R4 are important for imparting high potency while specificity is decided by R1/R3 fragment. We also checked the predictive ability of the dual-model by determining applicability domain using William's plot. Also, analysis of active molecules showed they show favorable substitutions that agree with the constructed dual-model. Thus, we have been successful in developing a single dual-response QSAR model to get an insight into various structural features influencing EGFR/HER2 activity.