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In Silico Pharmacokinetics Studies for Quinazolines Proposed as EGFR Inhibitors

Open Journal of Medicinal Chemistry 2015年第4期5卷 106-115页

作者： Gabriela Souza Fernandes Michelle Bueno de Moura Pereira Ana Cláudia Barbosa Marinho Brisa Machado Ana Carla Moreira Matheus Puggina de Freitas Karen Luise Lang joao eustáquio antunes Department of Medicine Federal University of Juiz de Fora Governador Valadares Brazil Department of Pharmacy Federal University of Juiz de Fora Governador Valadares Brazil Department of Chemistry Federal University of Lavras Lavras Brazil

In silico pharmacokinetics studies can aid the search for molecules with potential ability to be drug candidates. In this paper, a number of quinazoline candidates for epidermal growth factor receptor inhibitors—EGFR, important targets for the treatment of cancer, are computationally analyzed. The literature described that 69 quinazoline molecules were synthesized and the respective half maximum inhibitory concentrations (IC50) were obtained. A bilinear parabolic model was built to investigate the druglikeness by correlating the corresponding lipophilicities, which can be represented by the ideal Log P , with the optimal biological activity in terms of pIC50 values. Structural characteristics leading to improved pharmacokinetics parameters were then analyzed. Compound 56 exhibited the lowest IC50 and, therefore, it had the highest ability to inhibit the EGFR. In the present work, the most potent inhibitor 56 is not calculated to be the most promising drug candidate, since it’s out of the parabolic model obtained due to a Log P above 5, which is not within the expected optimum range. Finally, this work is an example of computational prediction that an experimentally, highly active EGFR inhibitor can be unsuccessful as drug candidate because of pitfalls in pharmacokinetics parameters.

关键词： Cancer Treatment Quinazoline Inhibitors Rational Drug Design Pharmacokinetics

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