{"created":"2023-05-15T15:02:44.547198+00:00","id":85066,"links":{},"metadata":{"_buckets":{"deposit":"4fe5d09c-525a-4d5c-a261-c31a6c63db69"},"_deposit":{"created_by":1,"id":"85066","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"85066"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00085066","sets":["1"]},"author_link":["1042645","1042647","1042644","1042649","1042646","1042648"],"item_8_biblio_info_7":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2022-02","bibliographicIssueDateType":"Issued"},"bibliographicIssueNumber":"5","bibliographicPageEnd":"1344","bibliographicPageStart":"1328","bibliographicVolumeNumber":"62","bibliographic_titles":[{"bibliographic_title":"Journal of Chemical Information and Modeling"}]}]},"item_8_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"A human immunodeficiency virus-1 (HIV-1)\nprotease is a homodimeric aspartic protease essential for the\nreplication of HIV. The HIV-1 protease is a target protein in drug\ndiscovery for antiretroviral therapy, and various inhibitor molecules\nof transition state analogues have been developed. However,\nserious drug-resistant mutants have emerged. For understanding\nthe molecular mechanism of the drug resistance, an accurate\nexamination of the impacts of the mutations on ligand binding and\nenzymatic activity is necessary. Here, we present a molecular\nsimulation study on the ligand binding of indinavir, a potent\ntransition state analogue inhibitor, to the wild-type protein and a V82T/I84V drug-resistant mutant of the HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free-energy optimization technique which combines a highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of the MM protein environment by long-time molecular dynamics simulations. Through the free-energy calculations of protonation states of catalytic groups at the binding pocket and of the ligand-binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug resistance through the direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.","subitem_description_type":"Abstract"}]},"item_8_publisher_8":{"attribute_name":"出版者","attribute_value_mlt":[{"subitem_publisher":"ACS Publications"}]},"item_8_relation_14":{"attribute_name":"DOI","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"10.1021/acs.jcim.1c01193","subitem_relation_type_select":"DOI"}}]},"item_8_relation_17":{"attribute_name":"関連サイト","attribute_value_mlt":[{"subitem_relation_type_id":{"subitem_relation_type_id_text":"https://pubs.acs.org/doi/abs/10.1021/acs.jcim.1c01193","subitem_relation_type_select":"URI"}}]},"item_8_source_id_9":{"attribute_name":"ISSN","attribute_value_mlt":[{"subitem_source_identifier":"1549-9596","subitem_source_identifier_type":"ISSN"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata only access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_14cb"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Masahiko, Taguchi"}],"nameIdentifiers":[{"nameIdentifier":"1042644","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ryo, Oyama"}],"nameIdentifiers":[{"nameIdentifier":"1042645","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Masahiro, Kaneso"}],"nameIdentifiers":[{"nameIdentifier":"1042646","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Shigehiko, Hayashi"}],"nameIdentifiers":[{"nameIdentifier":"1042647","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Masahiko, Taguchi","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1042648","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Ryo, Oyama","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"1042649","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"journal article","resourceuri":"http://purl.org/coar/resource_type/c_6501"}]},"item_title":"Hybrid QM/MM Free-Energy Evaluation of Drug-Resistant Mutational Effect on the Binding of an Inhibitor Indinavir to HIV‐1 Protease","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Hybrid QM/MM Free-Energy Evaluation of Drug-Resistant Mutational Effect on the Binding of an Inhibitor Indinavir to HIV‐1 Protease"}]},"item_type_id":"8","owner":"1","path":["1"],"pubdate":{"attribute_name":"公開日","attribute_value":"2021-09-29"},"publish_date":"2021-09-29","publish_status":"0","recid":"85066","relation_version_is_last":true,"title":["Hybrid QM/MM Free-Energy Evaluation of Drug-Resistant Mutational Effect on the Binding of an Inhibitor Indinavir to HIV‐1 Protease"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T17:21:30.503377+00:00"}