{"doi":"10.1371/journal.pone.0179936","title":"Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome","abstract":"Protein kinases are critical drug targets for treating a large variety of human diseases. Type-III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We hypothesize that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently, we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors.","journal":"PLOS ONE","year":2017,"id":340,"datarank":2.1880186369369765,"base_score":3.8712010109078907,"endowment":3.8712010109078907,"self_citation_contribution":0.5806801516361837,"citation_network_contribution":1.6073384853007928,"self_endowment_contribution":0.5806801516361837,"citer_contribution":1.6073384853007928,"corpus_percentile":null,"corpus_rank":null,"citation_count":47,"citer_count":35,"citers_with_citation_signal":31,"citers_with_endowment":31,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0494,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2017-06-19","fair_score":67.5,"fair_percentile":96.2,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":150,"name":"Lei Xie","orcid":"0000-0001-9051-2111","position":1,"is_corresponding":false},{"id":125,"name":"Philip  E. 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