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Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
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2014 (English)In: Acta Pharmacologica Sinica, ISSN 1671-4083, E-ISSN 1745-7254, Vol. 35, no 2, 301-310 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 35, no 2, 301-310 p.
Keyword [en]
epidermal growth factor receptor, tyrosine kinase, ensemble docking, ensemble-QSAR, drug design
National Category
Pharmacology and Toxicology Chemical Sciences
URN: urn:nbn:se:kth:diva-141957DOI: 10.1038/aps.2013.148ISI: 000330581300016ScopusID: 2-s2.0-84893633441OAI: diva2:699628

QC 20140228

Available from: 2014-02-28 Created: 2014-02-27 Last updated: 2014-02-28Bibliographically approved

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Sun, Xian-qiangTu, Yao-quan
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