{"id":"https://openalex.org/W4308368860","doi":"https://doi.org/10.1021/acs.jcim.2c01264","title":"Molecular Insights into the Heterotropic Allosteric Mechanism in Cytochrome P450 3A4-Mediated Midazolam Metabolism","display_name":"Molecular Insights into the Heterotropic Allosteric Mechanism in Cytochrome P450 3A4-Mediated Midazolam Metabolism","publication_year":2022,"publication_date":"2022-11-07","ids":{"openalex":"https://openalex.org/W4308368860","doi":"https://doi.org/10.1021/acs.jcim.2c01264","pmid":"https://pubmed.ncbi.nlm.nih.gov/36342224"},"language":"en","primary_location":{"id":"doi:10.1021/acs.jcim.2c01264","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.2c01264","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},"type":"article","indexed_in":["crossref","pubmed"],"open_access":{"is_oa":false,"oa_status":"closed","oa_url":null,"any_repository_has_fulltext":false},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5104688047","display_name":"Tingting Fu","orcid":"https://orcid.org/0000-0003-3597-625X"},"institutions":[{"id":"https://openalex.org/I194450716","display_name":"Jilin University","ror":"https://ror.org/00js3aw79","country_code":"CN","type":"education","lineage":["https://openalex.org/I194450716"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Tingting Fu","raw_affiliation_strings":["Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China","institution_ids":["https://openalex.org/I194450716"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5100718689","display_name":"Hong\u2010Xing Zhang","orcid":"https://orcid.org/0000-0001-5334-733X"},"institutions":[{"id":"https://openalex.org/I194450716","display_name":"Jilin University","ror":"https://ror.org/00js3aw79","country_code":"CN","type":"education","lineage":["https://openalex.org/I194450716"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Hongxing Zhang","raw_affiliation_strings":["Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"],"raw_orcid":"https://orcid.org/0000-0001-5334-733X","affiliations":[{"raw_affiliation_string":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China","institution_ids":["https://openalex.org/I194450716"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5009654446","display_name":"Qing\u2010Chuan Zheng","orcid":"https://orcid.org/0000-0003-2978-768X"},"institutions":[{"id":"https://openalex.org/I194450716","display_name":"Jilin University","ror":"https://ror.org/00js3aw79","country_code":"CN","type":"education","lineage":["https://openalex.org/I194450716"]}],"countries":["CN"],"is_corresponding":true,"raw_author_name":"Qingchuan Zheng","raw_affiliation_strings":["Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China","Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, China"],"raw_orcid":"https://orcid.org/0000-0003-2978-768X","affiliations":[{"raw_affiliation_string":"Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China","institution_ids":["https://openalex.org/I194450716"]},{"raw_affiliation_string":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun 130023, China","institution_ids":["https://openalex.org/I194450716"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":["https://openalex.org/A5009654446"],"corresponding_institution_ids":["https://openalex.org/I194450716"],"apc_list":null,"apc_paid":null,"fwci":0.8791,"has_fulltext":false,"cited_by_count":7,"citation_normalized_percentile":{"value":0.72605623,"is_in_top_1_percent":false,"is_in_top_10_percent":false},"cited_by_percentile_year":{"min":91,"max":98},"biblio":{"volume":"62","issue":"22","first_page":"5762","last_page":"5770"},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10375","display_name":"Pharmacogenetics and Drug Metabolism","score":0.9997000098228455,"subfield":{"id":"https://openalex.org/subfields/3004","display_name":"Pharmacology"},"field":{"id":"https://openalex.org/fields/30","display_name":"Pharmacology, Toxicology and Pharmaceutics"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10375","display_name":"Pharmacogenetics and Drug Metabolism","score":0.9997000098228455,"subfield":{"id":"https://openalex.org/subfields/3004","display_name":"Pharmacology"},"field":{"id":"https://openalex.org/fields/30","display_name":"Pharmacology, Toxicology and Pharmaceutics"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10908","display_name":"Analytical Chemistry and Chromatography","score":0.9976999759674072,"subfield":{"id":"https://openalex.org/subfields/1607","display_name":"Spectroscopy"},"field":{"id":"https://openalex.org/fields/16","display_name":"Chemistry"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}},{"id":"https://openalex.org/T10211","display_name":"Computational Drug Discovery Methods","score":0.9976000189781189,"subfield":{"id":"https://openalex.org/subfields/1703","display_name":"Computational Theory and Mathematics"},"field":{"id":"https://openalex.org/fields/17","display_name":"Computer Science"},"domain":{"id":"https://openalex.org/domains/3","display_name":"Physical Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/allosteric-regulation","display_name":"Allosteric regulation","score":0.9742408394813538},{"id":"https://openalex.org/keywords/cyp3a4","display_name":"CYP3A4","score":0.8295266628265381},{"id":"https://openalex.org/keywords/chemistry","display_name":"Chemistry","score":0.5636113286018372},{"id":"https://openalex.org/keywords/allosteric-enzyme","display_name":"Allosteric enzyme","score":0.5528725981712341},{"id":"https://openalex.org/keywords/cytochrome-p450","display_name":"Cytochrome P450","score":0.5170329213142395},{"id":"https://openalex.org/keywords/computational-biology","display_name":"Computational biology","score":0.4679402709007263},{"id":"https://openalex.org/keywords/drug-discovery","display_name":"Drug discovery","score":0.41124939918518066},{"id":"https://openalex.org/keywords/biophysics","display_name":"Biophysics","score":0.3563670516014099},{"id":"https://openalex.org/keywords/biochemistry","display_name":"Biochemistry","score":0.33854618668556213},{"id":"https://openalex.org/keywords/biology","display_name":"Biology","score":0.237844318151474},{"id":"https://openalex.org/keywords/enzyme","display_name":"Enzyme","score":0.23619195818901062}],"concepts":[{"id":"https://openalex.org/C166342909","wikidata":"https://www.wikidata.org/wiki/Q845326","display_name":"Allosteric regulation","level":3,"score":0.9742408394813538},{"id":"https://openalex.org/C109650736","wikidata":"https://www.wikidata.org/wiki/Q424440","display_name":"CYP3A4","level":4,"score":0.8295266628265381},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.5636113286018372},{"id":"https://openalex.org/C109964505","wikidata":"https://www.wikidata.org/wiki/Q3321436","display_name":"Allosteric enzyme","level":4,"score":0.5528725981712341},{"id":"https://openalex.org/C526171541","wikidata":"https://www.wikidata.org/wiki/Q407693","display_name":"Cytochrome P450","level":3,"score":0.5170329213142395},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.4679402709007263},{"id":"https://openalex.org/C74187038","wikidata":"https://www.wikidata.org/wiki/Q1418791","display_name":"Drug discovery","level":2,"score":0.41124939918518066},{"id":"https://openalex.org/C12554922","wikidata":"https://www.wikidata.org/wiki/Q7100","display_name":"Biophysics","level":1,"score":0.3563670516014099},{"id":"https://openalex.org/C55493867","wikidata":"https://www.wikidata.org/wiki/Q7094","display_name":"Biochemistry","level":1,"score":0.33854618668556213},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.237844318151474},{"id":"https://openalex.org/C181199279","wikidata":"https://www.wikidata.org/wiki/Q8047","display_name":"Enzyme","level":2,"score":0.23619195818901062}],"mesh":[{"descriptor_ui":"D001665","descriptor_name":"Binding Sites","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D001665","descriptor_name":"Binding Sites","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D001665","descriptor_name":"Binding Sites","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D003577","descriptor_name":"Cytochrome P-450 Enzyme System","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D003577","descriptor_name":"Cytochrome P-450 Enzyme System","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D003577","descriptor_name":"Cytochrome P-450 Enzyme System","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":false},{"descriptor_ui":"D008874","descriptor_name":"Midazolam","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D008874","descriptor_name":"Midazolam","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D008874","descriptor_name":"Midazolam","qualifier_ui":"Q000378","qualifier_name":"metabolism","is_major_topic":true},{"descriptor_ui":"D008874","descriptor_name":"Midazolam","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D008874","descriptor_name":"Midazolam","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D008874","descriptor_name":"Midazolam","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D008968","descriptor_name":"Molecular Conformation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D008968","descriptor_name":"Molecular Conformation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D008968","descriptor_name":"Molecular Conformation","qualifier_ui":null,"qualifier_name":null,"is_major_topic":false},{"descriptor_ui":"D051544","descriptor_name":"Cytochrome P-450 CYP3A","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D051544","descriptor_name":"Cytochrome P-450 CYP3A","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true},{"descriptor_ui":"D051544","descriptor_name":"Cytochrome P-450 CYP3A","qualifier_ui":"Q000737","qualifier_name":"chemistry","is_major_topic":true}],"locations_count":2,"locations":[{"id":"doi:10.1021/acs.jcim.2c01264","is_oa":false,"landing_page_url":"https://doi.org/10.1021/acs.jcim.2c01264","pdf_url":null,"source":{"id":"https://openalex.org/S167262187","display_name":"Journal of Chemical Information and Modeling","issn_l":"1549-9596","issn":["1549-9596","1549-960X"],"is_oa":false,"is_in_doaj":false,"is_core":true,"host_organization":"https://openalex.org/P4310320006","host_organization_name":"American Chemical Society","host_organization_lineage":["https://openalex.org/P4310320006"],"host_organization_lineage_names":["American Chemical Society"],"type":"journal"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of Chemical Information and Modeling","raw_type":"journal-article"},{"id":"pmid:36342224","is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/36342224","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Journal of chemical information and modeling","raw_type":null}],"best_oa_location":null,"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being","score":0.7599999904632568}],"awards":[{"id":"https://openalex.org/G2434464396","display_name":"\u4ee5\u54aa\u8fbe\u5511\u4ed1\u4e3a\u63a2\u9488\uff0c\u7ec6\u80de\u8272\u7d20P4503A4\u50ac\u5316\u4ee3\u8c22\u8fc7\u7a0b\u673a\u5236\u7684\u7406\u8bba\u7814\u7a76","funder_award_id":"22073036","funder_id":"https://openalex.org/F4320321001","funder_display_name":"National Natural Science Foundation of China"}],"funders":[{"id":"https://openalex.org/F4320321001","display_name":"National Natural Science Foundation of China","ror":"https://ror.org/01h0zpd94"}],"has_content":{"grobid_xml":false,"pdf":false},"content_urls":null,"referenced_works_count":58,"referenced_works":["https://openalex.org/W1651084065","https://openalex.org/W1999227893","https://openalex.org/W2015185599","https://openalex.org/W2021520922","https://openalex.org/W2038530231","https://openalex.org/W2057806291","https://openalex.org/W2058971275","https://openalex.org/W2076154818","https://openalex.org/W2086746579","https://openalex.org/W2090968259","https://openalex.org/W2106050611","https://openalex.org/W2132629607","https://openalex.org/W2142627320","https://openalex.org/W2147993766","https://openalex.org/W2150981663","https://openalex.org/W2156423252","https://openalex.org/W2159675211","https://openalex.org/W2165812419","https://openalex.org/W2166997231","https://openalex.org/W2270260897","https://openalex.org/W2296756275","https://openalex.org/W2323104785","https://openalex.org/W2329705955","https://openalex.org/W2404280981","https://openalex.org/W2543779459","https://openalex.org/W2567127730","https://openalex.org/W2590206926","https://openalex.org/W2741577472","https://openalex.org/W2798194035","https://openalex.org/W2897568450","https://openalex.org/W2911329269","https://openalex.org/W2922229918","https://openalex.org/W2939052792","https://openalex.org/W2952546689","https://openalex.org/W3002831763","https://openalex.org/W3007990684","https://openalex.org/W3022846064","https://openalex.org/W3035236133","https://openalex.org/W3097145107","https://openalex.org/W3108206087","https://openalex.org/W3118589682","https://openalex.org/W3135629526","https://openalex.org/W3153926159","https://openalex.org/W3160505939","https://openalex.org/W3167920054","https://openalex.org/W3174499032","https://openalex.org/W3195599083","https://openalex.org/W3213762098","https://openalex.org/W3213797785","https://openalex.org/W3216093432","https://openalex.org/W4220663239","https://openalex.org/W4221014530","https://openalex.org/W4221096825","https://openalex.org/W4226027583","https://openalex.org/W4238157267","https://openalex.org/W4283211422","https://openalex.org/W4285728050","https://openalex.org/W4287510345"],"related_works":["https://openalex.org/W2052504582","https://openalex.org/W2049682677","https://openalex.org/W2463850709","https://openalex.org/W2034301964","https://openalex.org/W2751232480","https://openalex.org/W1982170406","https://openalex.org/W2333603516","https://openalex.org/W2088091011","https://openalex.org/W5024670","https://openalex.org/W4308368860"],"abstract_inverted_index":{"Cytochrome":[0],"P450":[1,7],"3A4":[2],"(CYP3A4)":[3],"is":[4,18,38],"the":[5,21,66,121,128,131,137,144,147,165,174,178,181,212,226],"main":[6],"enzyme":[8],"for":[9,44,219],"drug":[10,45,221],"metabolism":[11],"and":[12,47,57,79,99,135,161,177,215],"drug-drug":[13],"interactions":[14],"(DDIs),":[15],"as":[16,223,225],"it":[17],"involved":[19],"in":[20,92,116,188,197],"metabolic":[22],"process":[23],"of":[24,27,33,69,102,106,123,130,139,146,168,207,228],"approximately":[25],"50%":[26],"drugs.":[28],"A":[29],"detailed":[30],"mechanistic":[31],"elucidation":[32],"DDIs":[34],"mediated":[35],"by":[36,185],"CYP3A4":[37,117],"commonly":[39],"believed":[40],"to":[41,64,143,192],"be":[42,193,217],"critical":[43],"optimization":[46],"rational":[48,220],"use.":[49],"Here,":[50],"two":[51,93,110],"typical":[52],"probes,":[53],"midazolam":[54],"(MDZ,":[55],"substrate)":[56],"testosterone":[58],"(TST,":[59],"allosteric":[60,72,152,182,230],"effector),":[61],"are":[62,155],"used":[63],"investigate":[65],"molecular":[67,76],"mechanism":[68],"CYP3A4-mediated":[70,208],"heterotropic":[71,166,209],"interactions,":[73],"through":[74],"conventional":[75],"dynamics":[77],"(cMD)":[78],"well-tempered":[80],"metadynamics":[81],"(WT-MTD)":[82],"simulations.":[83],"Distance":[84],"monitoring":[85],"shows":[86],"that":[87,157],"TST":[88,107,169,186],"can":[89,112,158],"stably":[90],"bind":[91],"potential":[94],"peripheral":[95],"sites":[96,111],"(Site":[97],"1":[98],"Site":[100,189,198],"2)":[101],"CYP3A4.":[103],"The":[104],"binding":[105,133,187],"at":[108,211],"these":[109],"induce":[113],"conformational":[114,124],"changes":[115],"flexible":[118],"loops":[119],"on":[120,170],"basis":[122],"analysis,":[125],"thereby":[126],"promoting":[127],"transition":[129],"MDZ":[132,140,171],"mode":[134],"affecting":[136],"ratio":[138],"metabolites.":[141],"According":[142],"results":[145],"residue":[148],"interaction":[149],"network,":[150],"multiple":[151],"communication":[153,179],"pathways":[154],"identified":[156],"provide":[159,203],"vivid":[160],"applicable":[162],"insights":[163],"into":[164],"allostery":[167,210],"metabolism.":[172],"Comparing":[173],"regulatory":[175],"effects":[176],"pathways,":[180],"effect":[183],"caused":[184],"2":[190],"seems":[191],"more":[194],"pronounced":[195],"than":[196],"1.":[199],"Our":[200],"findings":[201],"could":[202],"a":[204],"deeper":[205],"understanding":[206],"atomic":[213],"level":[214],"would":[216],"helpful":[218],"use":[222],"well":[224],"design":[227],"new":[229],"modulators.":[231]},"counts_by_year":[{"year":2026,"cited_by_count":2},{"year":2025,"cited_by_count":1},{"year":2024,"cited_by_count":4}],"updated_date":"2026-03-27T05:58:40.876381","created_date":"2025-10-10T00:00:00"}
