Structural Basis of AZD9291 Selectivity for EGFR T790M
| Autor: | Su-Jie Zhu, Je-Luen Li, Pelin Ayaz, Yibing Shan, Peng Zhao, Casey H Zhang, Xin Huang, Xiao-E Yan, Cai-Hong Yun, Ya-Chuang Wu, Ling Liang, David E. Shaw, Hwan Geun Choi |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Protein Conformation
Mutant Molecular Dynamics Simulation Crystallography X-Ray 01 natural sciences Molecular Docking Simulation 03 medical and health sciences T790M Drug Discovery Humans Point Mutation Osimertinib Protein Kinase Inhibitors 030304 developmental biology 0303 health sciences Acrylamides Aniline Compounds Kinase Chemistry Point mutation Rational design respiratory tract diseases 0104 chemical sciences ErbB Receptors 010404 medicinal & biomolecular chemistry Cancer research Molecular Medicine Selectivity |
| Zdroj: | Journal of medicinal chemistry. 63(15) |
| ISSN: | 1520-4804 |
| Popis: | AZD9291 (Osimertinib) is highly effective in treating EGFR-mutated non-small-cell lung cancers (NSCLCs) with T790M-mediated drug resistance. Despite the remarkable success of AZD9291, its binding pose with EGFR T790M remains unclear. Here, we report unbiased, atomic-level molecular dynamics (MD) simulations in which spontaneous association of AZD9291 with EGFR kinases having WT and T790M mutant gatekeepers was observed. Simulation-generated structural models suggest that the binding pose of AZD9291 with T790M differs from its binding pose with the WT, and that AZD9291 interacts extensively with the gatekeeper residue (Met 790) in T790M but not with Thr 790 in the WT, which explains why AZD9291 binds T790M with higher affinity. The MD simulation-generated models were confirmed by experimentally determined EGFR/T790M complex crystal structures. This work may facilitate the rational design of drugs that can overcome resistance mutations to AZD9291, and more generally it suggests the potential of using unbiased MD simulation to elucidate small-molecule binding poses. |
| Databáze: | OpenAIRE |
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