title: Identification of novel drug-resistant EGFR mutant inhibitors by in silico screening using comprehensive assessments of protein structures.
abstract: EGFR is a target protein for the treatment of non small cell lung cancer (NSCLC). The mutations associated with the activation of EGFR kinase activity, such as L858R and G719S, destabilize the inactive conformation of EGFR and are closely linked with the development of NSCLC. The additional T790M mutation reportedly causes drug resistance against the commercially available EGFR inhibitors, gefitinib and erlotinib. In this study, we searched for novel G719S/T790M EGFR inhibitors by a new in silico screening strategy, using two datasets. The results of in silico screening using protein-ligand docking are affected by the selection of 3D structure of the target protein. As the first strategy, we chose the 3D structures for in silico screening by test dockings using the G719S/T790M crystal structure, its molecular dynamics snapshots, and known inhibitors of the drug-resistant EGFR. In the second strategy, we selected the 3D structures by test dockings using all of the EGFR structures, regardless of the mutations, and all of the known EGFR inhibitors. Using each of the 3D structures selected by the strategies, 1000 compounds were chosen from the 71,588 compounds. Kinase assays identified 15 G719S/T790M EGFR inhibitors, including two compounds with novel scaffolds. Analyses of their structure-activity relationships revealed that interactions with the mutated Met790 residue specifically increase the inhibitory activity against G719S/T790M EGFR.
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sato
authors.forename: Hisami
authors.initials: H
authors.lastname: Watanabe
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuganezawa
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yuki
authors.forename: Junko
authors.initials: J
authors.lastname: Mikuni
authors.forename: Seiko
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Kukimoto-Niino
authors.forename: Takako
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Terazawa
authors.forename: Motoaki
authors.initials: M
authors.lastname: Wakiyama
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors