Computational studies of potent covalent inhibitors on wild type or T790M/L858R mutant epidermal growth factor receptor
| Autor: | Lishun Zhang, Jiajie Zhang, Zhonghuang Li, Tingting Zhang, Xuan Xu, Shaoyu Wu, Zichao Yang, Shanhe Wan, Huiwu Zhang, Hai-Kui Yang, Yangcheng Ai |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Lung Neoplasms
Stereochemistry Mutant Pharmaceutical Science 02 engineering and technology 030226 pharmacology & pharmacy 03 medical and health sciences T790M symbols.namesake 0302 clinical medicine Humans Epidermal growth factor receptor Protein Kinase Inhibitors EGFR inhibitors biology Chemistry Intermolecular force Wild type 021001 nanoscience & nanotechnology respiratory tract diseases ErbB Receptors Molecular Docking Simulation Covalent bond Mutation biology.protein symbols van der Waals force 0210 nano-technology |
| Zdroj: | European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 152 |
| ISSN: | 1879-0720 |
| Popis: | In this paper, we designed and synthesized two analog compounds M1 and T1 that have a Michael acceptor warhead. Although only slightly diversity existed in the structures of M1 and T1, their inhibitory activities against wild type epidermal growth factor receptor (EGFRWT) and T790M/L858R mutant epidermal growth factor receptor (EGFRT790M/L858R) were significant different. Thus, multiple computational approaches were applied to investigate the interactions between the compounds with EGFRWT and EGFRT790M/L858R in order to explore the effect of different compounds. The molecular docking and MD simulations were performed to study the intermolecular interactions between compounds and EGFR. The binding free energy revealed that M1-EGFRWT and M1-EGFRT790M/L858R complexes have stronger binding affinity compared with the corresponding T1-EGFRWT and T1-EGFRT790M/L858R complexes, respectively. And the binding free energy decompositions for each residue analysis indicated that the van der Waals interactions are the major contributor to enhance the compounds to bind with EGFR. In addition, covalent binding complexes of M1-EGFRWT and M1-EGFRT790M/L858R were constructed and studied. Moreover, quantum mechanics method was applied to investigate the reaction mechanism of covalent binding of the compound and EGFR. The results will provide the details of structural and energetic information to develop potent covalent EGFR inhibitors in the future. |
| Databáze: | OpenAIRE |
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