Investigating mutation-specific biological activities of small molecules using quantitative structure-activity relationship for epidermal growth factor receptor in cancer

- Activity of anti-cancer compounds against EGFR driver mutations are highly selective.
- Developed mutation-specific QSAR models with a correlation of 0.72-0.91 on jack-knife test.
- Aromaticity and hydrogen bond-related features are important in predicting biological activity of the compounds.
- Binding patterns and interactions of the compounds with EGFR mutants complemented QSAR models.

Epidermal Growth Factor Receptor (EGFR) is a potential drug target in cancer therapy. Missense mutations play major roles in influencing the protein function, leading to abnormal cell proliferation and tumorigenesis. A number of EGFR inhibitor molecules targeting ATP binding domain were developed for the past two decades. Unfortunately, they become inactive due to resistance caused by new mutations in patients, and previous studies have also reported noticeable differences in inhibitor binding to distinct known driver mutants as well. Hence, there is a high demand for identification of EGFR mutation-specific inhibitors. In our present study, we derived a set of anti-cancer compounds with biological activities against eight typical EGFR known driver mutations and developed quantitative structure-activity relationship (QSAR) models for each separately. The compounds are grouped based on their functional scaffolds, which enhanced the correlation between compound features and respective biological activities. The models for different mutants performed well with a correlation coefficient, (r) in the range of 0.72-0.91 on jack-knife test. Further, we analyzed the selected features in different models and observed that hydrogen bond and aromaticity-related features play important roles in predicting the biological activity of a compound. This analysis is complimented with docking studies, which showed the binding patterns and interactions of ligands with EGFR mutants that could influence their activities.

143