Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors

Abstract

Aim: To develop a novel 3D-QSAR approach for study of the epidermal growth factor receptor tyrosine kinase (EGFR TK) and its inhibitors. Methods: One hundred thirty nine EGFR TK inhibitors were classified into 3 clusters. Ensemble docking of these inhibitors with 19 EGFR TK crystal structures was performed. Three protein structures that showed the best recognition of each cluster were selected based on the docking results. Then, a novel QSAR (ensemble-QSAR) building method was developed based on the ligand conformations determined by the corresponding protein structures. Results: Compared with the 3D-QSAR model, in which the ligand conformations were determined by a single protein structure, ensemble-QSAR exhibited higher R2 (0.87) and Q2 (0.78) values and thus appeared to be a more reliable and better predictive model. Ensemble-QSAR was also able to more accurately describe the interactions between the target and the ligands. Conclusion: The novel ensemble-QSAR model built in this study outperforms the traditional 3D-QSAR model in rationality, and provides a good example of selecting suitable protein structures for docking prediction and for building structure-based QSAR using available protein structures.

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

“…Interestingly, Sun et al . [24] used clusters of 19 EGFR-TKIs complexed structures for docking in an effort to create an ensemble that can be applied in ligand-based drug design. In 40 surveyed studies (Table S1 in the supplemental information online), structure-based drug design was mainly used as a supporting method to estimate ligand pose or interaction energy.…”

Synthesis and pharmacological evaluation of novel epidermal growth factor receptor inhibitors against prostate tumor cells

“…The docking-ready 3D coordinates of the X-ray structure of EGFR kinase (PDB: 1XKK) and its cognate ligand were downloaded from the scPDB ( ). The present study selected the X-ray structure 1XKK as it had been successfully used in previous structure-based virtual screenings ( 14 , 15 ). A commercially available compound database from the Specs company ( ) was selected to screen against EGFR kinase.…”

Recent Progress in Pyrimido[5,4-d]pyrimidine Chemistry

“…Related QSAR studies included anilines 96a and b (14MI1). Falnidamol is demethylated during in vivo metabolism (02MI1).…”