Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries.

Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czech Republic; Central European Institute of Technology Brno University of Technology Purkynova 656 123 612 00 Brno Czech Republic

See more in PubMed

Verlinde C.L.M.J., Hol W.G.J. Structure-based drug design: progress, results and challenges. Structure. 1994;2:577–587. PubMed

Kanakaveti V. Quantitative structure-activity relationship in ligand based drug design: concepts and applications. In: Gromiha M.M., editor. Protein interactions: computational methods, analysis and applications. World Scientific; 2020. pp. 333–349.

Sledz P., Caflisch A. Protein structure-based drug design: from docking to molecular dynamics. Curr Opin Struct Biol. 2018;48:93–102. PubMed

Engel J. Hope and disappointment: covalent inhibitors to overcome drug resistance in non-small cell lung cancer. ACS Med Chem Lett. 2016;7:2–5. PubMed PMC

Lionta E. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr Top Med Chem. 2014;14:1923–1938. PubMed PMC

Cheng T. Structure-based virtual screening for drug discovery: a problem-centric review. AAPS J. 2012;14:133–141. PubMed PMC

Langdon S.R. Bioisosteric replacement and scaffold hopping in lead generation and optimization. Mol Inform. 2010;29:366–385. PubMed

Lo Y.-C. Machine learning in chemoinformatics and drug discovery. Drug Discov Today. 2018;23:1538–1546. PubMed PMC

Haddad Y. Rotamer dynamics: analysis of rotamers in molecular dynamics simulations of proteins. Biophys J. 2019;116:2062–2072. PubMed PMC

Smith M., Smith J.C. Repurposing therapeutics for COVID-19: supercomputer-based docking to the SARS-CoV-2 viral spike protein and viral spike protein–human ACE2 interface. ChemRxiv. 2020;11:2020. doi: 10.26434/chemrxiv.11871402.v4. [published online March] DOI

Buonerba C. Predictors of outcomes in patients with EGFR-mutated non-small cell lung cancer receiving EGFR tyrosine kinase inhibitors: a systematic review and meta-analysis. Cancers. 2019;11:1–18. PubMed PMC

Leonetti A. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121:725–737. PubMed PMC

Tan C.-S. Third generation EGFR TKIs: current data and future directions. Mol Cancer. 2018;17:1–14. PubMed PMC

Lategahn J. Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S. Chem Sci. 2019;10(46):10789–10801. PubMed PMC

Jia Y. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016;534(7605):129–132. PubMed PMC

Wang S. EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 2017;385:51–54. PubMed

To C. Single and dual targeting of mutant EGFR with an allosteric inhibitor. Cancer Discov. 2019;9:926–943. PubMed PMC

Oronsky B. Navigating the ‘No Man's Land’ of TKI-failed EGFR-mutated non-small cell lung cancer (NSCLC): a review. Neoplasia. 2018;20:92–98. PubMed PMC

Rebuzzi S.E. Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives. Crit Rev Oncol Hematol. 2020;146:1–10. PubMed

Le Tourneau C. Molecular profiling in precision medicine oncology. Nat Med. 2019;25:711–712. PubMed

Guardiola S. A third shot at EGFR: new opportunities in cancer therapy. Trends Pharmacol Sci. 2019;40:941–955. PubMed

Chen Y. Discovery of new thieno 3,2-d pyrimidine derivatives targeting EGFR(L858R/T790M) NSCLCs by the conformation constrained strategy. Eur J Med Chem. 2020;199:1–13. PubMed

Karnik K.S. Development of triple mutant T790M/C797S allosteric EGFR inhibitors: a computational approach. J Biomol Struct Dyn. 2020 doi: 10.1080/07391102.2020.1786460. [published online July 1, 2020] PubMed DOI

Sun X.Q. Structure-based ensemble-QSAR model: a novel approach to the study of the EGFR tyrosine kinase and its inhibitors. Acta Pharmacol Sin. 2014;35:301–310. PubMed PMC

Zhou W. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature. 2009;462(7276):1070–1074. PubMed PMC

Kong L.-L. Structural pharmacological studies on EGFR T790M/C797S. Biochem Biophys Res Commun. 2017;488:266–272. PubMed

Xu G. Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases. Bioorg Med Chem Lett. 2008;18:3495–34999. PubMed

Gajiwala K.S. Insights into the aberrant activity of mutant EGFR kinase domain and drug recognition. Structure. 2013;21:209–219. PubMed

Zhu S.-J. Structural insights into drug development strategy targeting EGFR T790M/C797S. Oncotarget. 2018;9(17):13652–13665. PubMed PMC

Novotny C.J. Overcoming resistance to HER2 inhibitors through state-specific kinase binding. Nat Chem Biol. 2016;12:923–930. PubMed PMC

Wang A. Discovery of (R)-1-(3-(4-amino-3-(3-chloro-4-(pyridin-2-ylmethoxy) phenyl)-1 H-pyrazolo [3,4-d] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one (CHMFL-EGFR-202) as a novel irreversible EGFR mutant kinase inhibitor with a distinct binding mode. J Med Chem. 2017;60:2944–2962. PubMed

Hu C. Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode. Oncotarget. 2017;8:18359–18372. PubMed PMC

Foster S.A. Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell. 2016;29:477–493. PubMed

Yun C.-H. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007;11:217–227. PubMed PMC

Tan L. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc Natl Acad Sci U S A. 2014;111(45):4869–4877. PubMed PMC

Peng Y.-H. Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. J Med Chem. 2013;56:3889–3903. PubMed

Haddad Y. Ten quick tips for homology modeling of high-resolution protein 3D structures. PLoS Comp Biol. 2020;16:1–19. PubMed PMC

Zemla A. LGA: a method for finding 3D similarities in protein structures. Nucleic Acids Res. 2003;31(13):3370–3374. PubMed PMC

Zhang Y., Skolnick J. TM-align: a protein structure alignment algorithm based on the TM-score. Nucleic Acids Res. 2005;33:2302–2309. PubMed PMC

A rotamer relay information system in the epidermal growth factor receptor-drug complexes reveals clues to new paradigm in protein conformational change